Anhydrous and Hemihydrate Crystalline Forms of an (R)-Baclofen Prodrug, Methods of Synthesis and Methods of Use

ABSTRACT

Crystalline (3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoic acid anhydrate and crystalline (3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoic acid hemihydrate, pharmaceutical compositions comprising such compounds, methods of making and methods of using the same are disclosed.

This application claims the benefit under 35 U.S.C. §119(e), of U.S.Provisional Patent Application No. 61/508,286 filed Aug. 11, 2011, whichis incorporated herein by reference in its entirety.

FIELD

Crystalline(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid anhydrate and crystalline(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid hemihydrate, pharmaceutical compositions comprising such compounds,methods of making such compounds and methods of using such compounds aredisclosed.

BACKGROUND

In general, crystalline forms of drugs are utilized in dosage formsrather than amorphous forms of drugs, in part, because of their superiorstability. For example, in many situations, an amorphous drug convertsto a crystalline drug form upon storage. Because amorphous andcrystalline forms of a drug typically have different physical/chemicalproperties, potencies and/or bioavailabilities, such interconversion isundesirable for safety reasons in pharmaceutical administration.

Polymorphs are crystals of the same molecule which have differentphysical properties because the crystal lattice contains a differentarrangement of molecules. For example, certain polymorphs can includedifferent hydration states that incorporate water into the crystallinestructure without chemical alteration of the molecule itself. In thatregard, certain compounds can exist in anhydrous and hydrated forms,where the hydrated forms can include, for example, hydrates, dihydrates,trihydrates, and the like, or partial hydrates such as hemihydrates. Thedifferent physical properties exhibited by polymorphs can affectimportant pharmaceutical parameters such as storage, stability,compressibility, density (important in formulation and productmanufacturing) and dissolution rates (important in determiningbioavailability). Stability differences may result from changes inchemical reactivity (e.g., differential hydrolysis or oxidation, suchthat a dosage form discolors more rapidly when the dosage form containsone polymorph rather than another polymorph), mechanical changes (e.g.,tablets crumble on storage as a kinetically favored crystalline formconverts to a thermodynamically more stable crystalline form) or both(e.g., tablets of one polymorph are more susceptible to breakdown athigh humidity). Solubility differences between polymorphs may, inextreme situations, result in transitions to crystalline forms that lackpotency and/or are toxic. In addition, the physical properties of aparticular crystalline form may be important in pharmaceuticalprocessing. For example, one particular crystalline form may formsolvates more readily or may be more difficult to filter and wash freeof impurities than other forms (e.g., particle shape and sizedistribution might be different between one crystalline form relative toother forms).

Regulatory agencies such as the United States Food and DrugAdministration closely regulate the polymorphic content of the activecomponent of a drug in solid dosage forms. In general, regulatoryagencies require batch-by-batch monitoring for polymorphic drugs ifanything other than the pure, thermodynamically preferred polymorph ismarketed. Accordingly, medical and commercial reasons favor synthesizingand marketing the most thermodynamically stable polymorph of acrystalline drug substance in solid drugs, which is substantially freeof other, less favored polymorphs.

(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid, (1),

is a prodrug of the GABA_(B) agonist, (R)-baclofen.(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid, (1) exhibits high bioavailability as R-baclofen when dosed eitherorally or directly into the colon of a mammal (see, for example, Gallopet al., U.S. Pat. Nos. 7,109,239 and 7,227,028).

SUMMARY

Crystalline(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid anhydrate and crystalline(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid hemihydrate are disclosed.

In a first aspect, crystalline(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid hemihydrate, which exhibits characteristic scattering angles (2θ)at least at 4.04°±0.2°, 6.47°±0.2°, 15.68°±0.2°, 18.91°±0.2° and22.42°±0.2° in an X-ray powder diffractogram measured using Cu-K_(α)radiation, is provided.

In a second aspect, pharmaceutical compositions are provided comprisingcrystalline(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid hemihydrate, which exhibits characteristic scattering angles (2θ)at least at 4.04°±0.2°, 6.47°±0.2°, 15.68°±0.2°, 18.91°±0.2° and22.42°±0.2° in an X-ray powder diffractogram measured using Cu-K_(α)radiation and a pharmaceutically acceptable vehicle.

In a third aspect, methods of preparing crystalline(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid hemihydrate, which exhibits characteristic scattering angles (2θ)at least at 4.04°±0.2°, 6.47°±0.2°, 15.68°±0.2°, 18.91°±0.2° and22.42°±0.2° in an X-ray powder diffractogram measured using Cu-K_(α)radiation are provided, by steps comprising providing a solutioncomprising1-((2,5-dioxopyrrolidin-1-yl-oxycarbonyloxy)-2-methylpropyl-2-methylpropanoateprepared as a racemic mixture, (R)-baclofen, water and a solvent; andadjusting the temperature of the solution or suspension to providecrystalline(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid hemihydrate.

In a fourth aspect, methods of treating a disease or disorder in apatient are provided comprising administering to a patient in need ofsuch treatment a therapeutically effective amount of a pharmaceuticalcomposition comprising crystalline(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid hemihydrate, wherein the disease or disorder is selected fromspasticity, gastroesophageal reflux disease, emesis, cough, substanceaddiction and abuse, neuropathic pain and musculoskeletal pain.

In a fifth aspect, kits are provided comprising a pharmaceuticalcomposition comprising crystalline(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid hemihydrate and instructions for administering the pharmaceuticalcomposition to a patient in need thereof for treating a disease ordisorder chosen from selected from spasticity, gastroesophageal refluxdisease, emesis, cough, substance addiction and abuse, neuropathic painand musculoskeletal pain.

In a sixth aspect, crystalline(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid anhydrate, which exhibits characteristic scattering angles (2θ) atleast at 4.33°±0.2°, 4.76°±0.2°, 11.06°±0.2° and 11.61°±0.2° in an X-raypowder diffractogram measured using Cu-K_(α) radiation, is provided.

In a seventh aspect, pharmaceutical compositions are provided comprisingcrystalline(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid anhydrate, which exhibits characteristic scattering angles (2θ) atleast at 4.33°±0.2°, 4.76°±0.2°, 11.06°±0.2° and 11.61°±0.2° in an X-raypowder diffractogram measured using Cu-K_(α) radiation and apharmaceutically acceptable vehicle.

In a eighth aspect, methods of preparing crystalline(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid anhydrate, which exhibits characteristic scattering angles (2θ) atleast at 4.33°±0.2°, 4.76°±0.2°, 11.06°±0.2° and 11.61°±0.2° in an X-raypowder diffractogram measured using Cu-K_(α) radiation are provided, bysteps comprising providing a solution comprising1-((2,5-dioxopyrrolidin-1-yl-oxycarbonyloxy)-2-methylpropyl-2-methylpropanoateprepared as a racemic mixture, (R)-baclofen, water and a solvent;adjusting the temperature of the solution or suspension to providecrystalline(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid hemihydrate and(3R)-4-{[(1R)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid; and converting crystalline(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid hemihydrate into crystalline(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid anhydrate by drying and/or by recrystallization.

In a ninth aspect, methods of treating a disease or disorder in apatient are provided comprising administering to a patient in need ofsuch treatment a therapeutically effective amount of a pharmaceuticalcomposition comprising crystalline(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid anhydrate, wherein the disease or disorder is selected fromspasticity, gastroesophageal reflux disease, emesis, cough, substanceaddiction and abuse, neuropathic pain and musculoskeletal pain.

In a tenth aspect, kits are provided comprising a pharmaceuticalcomposition comprising crystalline(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid anhydrate and instructions for administering the pharmaceuticalcomposition to a patient in need thereof for treating a disease ordisorder chosen from selected from spasticity, gastroesophageal refluxdisease, emesis, cough, substance addiction and abuse, neuropathic painand musculoskeletal pain.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows an X-ray powder diffractogram of crystalline(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid hemihydrate.

FIG. 2 shows a Raman spectrum of crystalline(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid hemihydrate in the region from 50 to 2000 cm⁻¹.

FIG. 3 shows an X-ray powder diffractogram of crystalline(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid anhydrate.

FIG. 4 shows a Raman spectrum of crystalline(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid anhydrate in the region from 50 to 2000 cm⁻¹.

DETAILED DESCRIPTION Definitions

“Bioavailability” refers to the amount of a drug that reaches thesystemic circulation of a patient following administration of the drugor prodrug thereof to the patient and may be determined by evaluating,for example, the plasma or blood concentration-versus-time profile for adrug. Parameters useful in characterizing a plasma or bloodconcentration-versus-time curve include the area under the curve (AUC),the time to maximum concentration (T_(max)), and the maximum drugconcentration (C_(max)), where C_(max) is the maximum concentration of adrug in the plasma or blood of a patient following administration of adose of the drug or prodrug thereof to the patient, and T_(max) is thetime to the maximum concentration (C_(max)) of a drug in the plasma orblood of a patient following administration of a dose of the drug orprodrug thereof to the patient.

“Crystalline” means having a regularly repeating arrangement ofmolecules.

“Crystalline(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid anhydrate” refers to a compound in which crystalline(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid is not associated with water molecules. Other chemical names forcrystalline(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid anhydrate include, without limitation, anhydrous crystalline(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid.

“Crystalline(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid hemihydrate” refers to a compound in which crystalline(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid is associated with water molecules, including fractional watermolecules. For example, crystalline(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid hemihydrate may contain less than one molar fraction of water,including fractional moles of water, per mole of crystalline(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid. In some embodiments, crystalline(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid hemihydrate contains one-half of one molar fraction of water permole of crystalline(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid. The molecules of water may be incorporated into the crystallattice or loosely bound to the crystal lattice. In certain embodiments,the fractional equivalent of one-half molecule of water per molecule ofcrystalline(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid is incorporated into the crystalline lattice and any additionalwater content is bound to the exterior of the crystalline lattice.

“Disease” refers to a disease, disorder, condition, symptom, orindication. This term is used interchangeably with the phrase “diseaseor disorder.”

“Dosage form” refers to a form of a formulation that contains an amountof active agent or prodrug of an active agent, for example the(R)-baclofen prodrug(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid (1), which can be administered to a patient to achieve atherapeutic effect. An oral dosage form is intended to be administeredto a patient via the mouth and swallowed. Examples of oral dosage formsinclude capsules, tablets, and liquid suspensions. A dose of a drug mayinclude one or more dosage forms administered simultaneously or over aperiod of time.

“Patient” includes mammals, such as for example, humans.

“Pharmaceutical composition” refers to a composition comprising at leastone compound provided by the present disclosure and at least onepharmaceutically acceptable vehicle with which the compound isadministered to a patient.

“Pharmaceutically acceptable” refers to approved or approvable by aregulatory agency of a federal or a state government, listed in the U.S.Pharmacopeia, or listed in other generally recognized pharmacopeia foruse in mammals, including humans.

“Pharmaceutically acceptable vehicle” refers to a pharmaceuticallyacceptable diluent, a pharmaceutically acceptable adjuvant, apharmaceutically acceptable excipient, a pharmaceutically acceptablecarrier, or a combination of any of the foregoing, with whichcrystalline(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid anhydrate and/or crystalline(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid hemihydrate can be administered to a patient, which does notdestroy the pharmacological activity thereof, and which is nontoxic whenadministered in doses sufficient to provide a therapeutically effectiveamount of one or both of the compounds.

“Prodrug” refers to a derivative of an active compound (such as a drug)that undergoes a transformation under the conditions of use, such aswithin the body, to release the active compound or drug. Prodrugs arefrequently, but not necessarily, pharmacologically inactive untilconverted into the active compound or drug. Prodrugs can be obtained bybonding a promoiety (defined herein), typically via a functional group,to a drug. For example, the (R)-baclofen prodrug(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid (1) is metabolized within a patient's body to form the parent drug(R)-baclofen.

“Promoiety” refers to a group bonded to a drug, typically to afunctional group of the drug, via one or more bonds that are cleavableunder specified conditions of use. The bond(s) between the drug andpromoiety may be cleaved by enzymatic or non-enzymatic means. Under theconditions of use, for example following administration to a patient,the bond(s) between the drug and promoiety may be cleaved to release theparent drug. The cleavage of the promoiety may proceed spontaneously,such as via a hydrolysis reaction, or may be catalyzed or induced byanother agent, such as by an enzyme, by light, by acid, or by a changeof or exposure to a physical or environmental parameter, such as achange of temperature, pH, etc. The agent may be endogenous to theconditions of use, such as an enzyme present in the systemic circulationto which the prodrug is administered or the acidic conditions of thestomach, or the agent may be supplied exogenously. For example, thepromoiety of(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid is:

“Sustained release” refers to release of a therapeutic or preventiveamount of a drug or an active metabolite thereof over a period of timethat is longer than that of an immediate release formulation of thedrug. For oral formulations, the term “sustained release” typicallymeans release of the drug within the gastrointestinal tract lumen over atime period ranging, for example, from about 2 to about 30 hours, and incertain embodiments, over a time period ranging from about 4 to about 24hours. Sustained release formulations achieve therapeutically effectiveconcentrations of the drug in the systemic circulation over a prolongedperiod of time relative to that achieved by oral administration of animmediate release formulation of the drug.

“Therapeutically effective amount” refers to the amount of a compoundthat, when administered to a subject for treating a disease or disorder,or at least one of the clinical symptoms of a disease or disorder, issufficient to affect such treatment of the disease, disorder, orsymptom. A “therapeutically effective amount” can vary depending, forexample, on the compound, the disease, disorder, and/or symptoms of thedisease or disorder, severity of the disease, disorder, and/or symptomsof the disease or disorder, the age, weight, and/or health of thepatient to be treated, and the judgment of the prescribing physician. Atherapeutically effective amount in any given instance can be readilyascertained by those skilled in the art and/or is capable ofdetermination by routine experimentation.

“Treating” or “treatment” of any disease or disorder refers to arrestingor ameliorating a disease, disorder, or at least one of the clinicalsymptoms of a disease or disorder, reducing the risk of acquiring adisease, disorder, or at least one of the clinical symptoms of a diseaseor disorder, reducing the development of a disease, disorder or at leastone of the clinical symptoms of the disease or disorder, or reducing therisk of developing a disease or disorder or at least one of the clinicalsymptoms of a disease or disorder. “Treating” or “treatment” also refersto inhibiting the disease or disorder, either physically, (e.g.,stabilization of a discernible symptom), physiologically, (e.g.,stabilization of a physical parameter), or both, and to inhibiting atleast one physical parameter which may or may not be discernible to thepatient. In certain embodiments, “treating” or “treatment” refers todelaying the onset of the disease or disorder or at least one or moresymptoms thereof in a patient which may be exposed to or predisposed toa disease or disorder even though that patient does not yet experienceor display symptoms of the disease or disorder.

Reference is now made in detail to certain embodiments of compounds,dosage forms, compositions, methods of synthesis and methods of use. Thedisclosed embodiments are not intended to be limiting of the claims. Tothe contrary, the claims are intended to cover all alternatives,modifications, and equivalents.

Crystalline(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid

(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid (1) has the following structure:

The synthesis of(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid has been previously described in Gallop et al., U.S. Pat. Nos.7,109,239 and 7,227,028, and in Gallop et al., PCT Publication No. WO2005/019163 (see, e.g., PCT Publication No. WO 2005/019163, Example 82).A crystalline form of(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid has also been previously described (see, e.g., PCT Publication Nos.WO 2008/086492 and WO 2009/096985). It is believed that the crystallineform disclosed in these publications is the anhydrate polymorph of(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid. The x-ray powder diffractogram data of the anhydrate presented inthis disclosure has not been previously described.

The inventors of the present disclosure have now discovered that ahemihydrate form of crystalline(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid exists. The hemihydrate polymorph is also disclosed herein. Thus,crystalline(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid can be prepared in more than one polymorphic crystalline form.

Crystalline(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid hemihydrate

In certain embodiments, crystalline(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid exists as a hemihydrate. Crystalline(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid hemihydrate is a solid exhibiting a highly ordered crystallinelattice as evidenced by an extensive pattern of both low-angle andhigh-angle reflections within the X-ray powder diffraction (XRPD)diffractogram.

Reference to crystalline(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid hemihydrate includes all possible tautomeric forms of theconventional chemical structure for this compound and all isotopicallylabeled derivatives of this compound (e.g., ²H, ³H, ¹³C, ¹⁴C, ¹⁵N, ¹⁷O,¹⁸O, etc.).

In certain embodiments, crystalline(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid hemihydrate exhibits characteristic scattering angles (2θ) at leastat 4.04°±0.2°, 6.47°±0.2°, 15.68°±0.2°, 18.91°±0.2° and 22.42°±0.2° inan X-ray powder diffractogram measured using Cu-K_(α) radiation.

In certain embodiments, crystalline(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid hemihydrate exhibits characteristic scattering angles (2θ) at leastat 4.04°±0.2°, 6.47°±0.2°, 9.46°±0.2°, 10.10°±0.2°, 10.87°±0.2°,12.88°±0.2°, 15.68°±0.2°, 18.91°±0.2°, 19.96°±0.2°, 20.23°±0.2°,22.42°±0.2°, 28.07°±0.2° and 28.53°±0.2° in an X-ray powderdiffractogram measured using Cu-K_(α) radiation.

In certain embodiments, crystalline(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid hemihydrate exhibits characteristic scattering angles (2θ) at leastat 4.04°±0.2°, 6.47°±0.2°, 7.97°±0.2°, 9.46°±0.2°, 10.10°±0.2°,10.87°±0.2°, 12.88°±0.2°, 15.68°±0.2°, 16.72°±0.2°, 18.16°±0.2°,18.91°±0.2°, 19.33°±0.2°, 19.96°±0.2°, 20.23°±0.2°, 20.62°±0.2°,21.76°±0.2°, 22.42°±0.2°, 23.55°±0.2°, 24.02°±0.2°, 25.13°±0.2°,25.61°±0.2°, 26.09°±0.2°, 28.07°±0.2°, 28.53°±0.2°, 29.87°±0.2°,30.45°±0.2°, 30.74°±0.2°, 31.52°±0.2°, 32.60°±0.2°, 35.94°±0.2° and36.63°±0.2° in an X-ray powder diffractogram measured using Cu-K_(α)radiation.

In certain embodiments, crystalline(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid hemihydrate exhibits the characteristic scattering angles (2θ) inan X-ray powder diffractogram measured using Cu-K_(α) radiation shown inFIG. 1.

In certain embodiments, crystalline(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid hemihydrate exhibits a strong characteristic Raman spectrum band at110 cm⁻¹.

In certain embodiments, crystalline(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid hemihydrate exhibits characteristic Raman spectrum bands at leastat 110 cm⁻¹ and 84 cm⁻¹.

In certain embodiments, crystalline(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid hemihydrate exhibits characteristic Raman spectrum bands at leastat 779 cm⁻¹, 110 cm⁻¹ and 84 cm⁻¹.

In certain embodiments, crystalline(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid hemihydrate exhibits characteristic Raman spectrum bands at leastat 1744 cm⁻¹, 1600 cm⁻¹, 1453 cm⁻¹, 1290 cm⁻¹, 1238 cm⁻¹, 1201 cm⁻¹, 954cm⁻¹, 872 cm⁻¹, 779 cm⁻¹, 635 cm⁻¹, 362 cm⁻¹, 315 cm⁻¹, 110 cm⁻¹ and 84cm⁻¹.

In certain embodiments, crystalline(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid hemihydrate exhibits the characteristic Raman spectrum in theregion from 50 cm⁻¹ to 2000 cm⁻¹ shown in FIG. 2.

Crystalline(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid hemihydrate can be characterized by the presence of two phasechanges upon thermal decomposition. For example, in certain embodimentstwo points of thermal decomposition can be observed via TG-FTIRanalysis. Additionally, in certain embodiments two melting point peakscan be observed using DSC analysis. The first phase transition can beattributed to the loss of water, which is characteristic of thehemihydrate polymorph. In certain embodiments, both phase changes can beattributable to the hemihydrate from of crystalline(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid.

In certain embodiments, crystalline(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid hemihydrate is generated at room temperature in anacetonitrile/water mixture having a critical water activity (a_(wct)) ofgreater than or equal to about 0.75±0.05. In certain embodiments,crystalline(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid hemihydrate is generated at room temperature in anacetonitrile/water mixture having a water activity (a_(w)) of about 0.8.In certain embodiments, crystalline(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid hemihydrate is generated at room temperature in anacetonitrile/water mixture having a a_(w) of about 0.9. In certainembodiments, crystalline(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid hemihydrate is generated at room temperature in anacetonitrile/water mixture having a a_(w) selected from about 0.8 andabout 0.9.

In certain embodiments, crystalline(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid hemihydrate undergoes thermal decomposition and loses about 2.1% ofits total weight at a temperature ranging from about 80° C. to about130° C. using a thermogravimetric analyzer (TG) coupled with aFourier-transform infrared (FTIR) spectrometer at a scan rate of about10 K/min. In some embodiments, the 2.1% weight loss is attributable towater loss.

In certain embodiments, crystalline(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid hemihydrate undergoes thermal decomposition at a temperatureranging from about 170° C. to about 190° C. using a thermogravimetricanalyzer (TG) coupled with a Fourier-transform infrared (FTIR)spectrometer at a scan rate of about 10 K/min.

In certain embodiments, crystalline(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid hemihydrate undergoes a first thermal decomposition at atemperature ranging from about 80° C. to about 130° C., and undergoes asecond thermal decomposition at a temperature ranging from about 170° C.to about 190° C., using a thermogravimetric analyzer (TG) coupled with aFourier-transform infrared (FTIR) spectrometer at a scan rate of about10 K/min. In certain embodiments, crystalline(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid hemihydrate loses about 2.1% of its total weight during the firstthermal decomposition. In some embodiments, the 2.1% weight loss isattributable to water loss.

In certain embodiments, crystalline(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid hemihydrate undergoes a melt/phase transition at a temperatureranging from about 90° C. to about 110° C. using differential scanningcalorimetry at a heating rate of 20 K/min. In certain embodiments thethermal decomposition occurs at about 100° C. and in certain embodimentsat about 99.8° C. In certain embodiments, crystalline(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid hemihydrate undergoes a melt/phase transition at a temperatureranging from about 105° C. to about 125° C. using differential scanningcalorimetry at a heating rate of 20 K/min. In certain embodiments thethermal decomposition occurs at about 115° C. and in certain embodimentsat about 114.8° C.

In certain embodiments, crystalline(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid hemihydrate undergoes a first melt/phase transition at atemperature ranging from about 90° C. to about 110° C., and alsoundergoes a second melt/phase transition at a temperature ranging fromabout 105° C. to about 125° C. using differential scanning calorimetryat a heating rate of 20 K/min. In certain embodiments the first thermaldecomposition occurs at about 100° C. and the second thermaldecomposition occurs at about 115° C. In certain embodiments the firstthermal decomposition occurs at about 99.8° C. and the second thermaldecomposition occurs at about 114.8° C.

In certain embodiments, crystalline(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid hemihydrate is hygroscopic. In certain embodiments, crystalline(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid hemihydrate is slightly hygroscopic above about 60% relativehumidity. In certain embodiments, crystalline(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid hemihydrate comprises from about 2 wt %-about 3 wt % water. Incertain embodiments, crystalline(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid hemihydrate contains about 2.15 wt % water at 50% relative humidityas measured by dynamic vapor sorption. In certain embodiments,crystalline(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid hemihydrate contains about 3 wt % water at 95% relative humidity asmeasured by dynamic vapor sorption.

Crystalline(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid anhydrate

In certain embodiments, crystalline(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid exists as an anhydrate. Crystalline(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid anhydrate is a solid exhibiting a highly ordered crystallinelattice as evidenced by an extensive pattern of both low-angle andhigh-angle reflections within the X-ray powder diffraction (XRPD)diffractogram

Reference to crystalline(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid anhydrate includes all possible tautomeric forms of theconventional chemical structure for this compound and all isotopicallylabeled derivatives of this compound (e.g., ²H, ³H, ¹³C, ¹⁴C, ¹⁵N, ¹⁷O,¹⁸O, etc.).

In certain embodiments, crystalline(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid anhydrate exhibits characteristic scattering angles (2θ) at leastat 4.33°±0.2°, 4.76°±0.2°, 11.06°±0.2° and 11.61°±0.2° in an X-raypowder diffractogram measured using Cu-K_(α) radiation.

In certain embodiments, crystalline(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid anhydrate exhibits characteristic scattering angles (2θ) at leastat 4.33°±0.2°, 4.76°±0.2°, 5.83°±0.2°, 9.07°±0.2°, 9.46°±0.2°,10.54°±0.2°, 11.06°±0.2°, 11.61°±0.2°, 12.94°±0.2°, 17.46°±0.2°,17.84°±0.2°, 18.01°±0.2°, 19.36°±0.2°, 20.01°±0.2° and 21.26°±0.2° in anX-ray powder diffractogram measured using Cu-K_(α) radiation.

In certain embodiments, crystalline(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid anhydrate exhibits characteristic scattering angles (2θ) at leastat 4.33°±0.2°, 4.76°±0.2°, 5.83°±0.2°, 6.93°±0.2°, 9.07°±0.2°,9.46°±0.2°, 10.54°±0.2°, 11.06°±0.2°, 11.61°±0.2°, 12.94°±0.2°,15.25°±0.2°, 16.55°±0.2°, 17.46°±0.2°, 17.84°±0.2°, 18.01°±0.2°,18.41°±0.2°, 18.69°±0.2°, 18.93°±0.2°, 19.36°±0.2°, 20.01°±0.2°,20.46°±0.2°, 21.26°±0.2°, 21.75°±0.2°, 22.19°±0.2°, 22.56°±0.2°,23.35°±0.2°, 23.85°±0.2°, 24.84°±0.2°, 25.96°±0.2°, 26.78°±0.2°,27.29°±0.2°, 28.69°±0.2°, 29.39°±0.2°, 31.22°±0.2°, 32.35°±0.2°,33.47°±0.2°, 34.62°±0.2° and 36.08°±0.2° in an X-ray powderdiffractogram measured using Cu-K_(α) radiation.

In certain embodiments, crystalline(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid anhydrate exhibits the characteristic scattering angles (2θ) in anX-ray powder diffractogram measured using Cu-K_(α) radiation shown inFIG. 3.

In certain embodiments, crystalline(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid anhydrate exhibits a strong characteristic Raman spectrum band at119 cm⁻¹.

In certain embodiments, crystalline(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid anhydrate exhibits characteristic Raman spectrum bands at least at119 cm⁻¹ and 85 cm⁻¹.

In certain embodiments, crystalline(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid anhydrate exhibits characteristic Raman spectrum bands at least at1599 cm⁻¹, 1447 cm⁻¹, 798 cm⁻¹, 119 cm⁻¹ and 85 cm⁻¹.

In certain embodiments, crystalline(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid anhydrate exhibits characteristic Raman spectrum bands at least at1747 cm⁻¹, 1599 cm⁻¹, 1447 cm⁻¹, 1412 cm⁻¹, 1335 cm⁻¹, 1203 cm⁻¹, 1092cm⁻¹, 954 cm⁻¹, 868 cm⁻¹, 798 cm⁻¹, 637 cm⁻¹, 401 cm⁻¹, 348 cm⁻¹, 317cm⁻¹, 244 cm⁻¹, 119 cm⁻¹ and 85 cm⁻¹.

In certain embodiments, crystalline(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid anhydrate exhibits the characteristic Raman spectrum in the regionfrom 50 cm⁻¹ to 2000 cm⁻¹ shown in FIG. 4.

In certain embodiments, crystalline(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid anhydrate is generated at room temperature in an acetonitrile/watermixture having a critical water activity (a_(wct)) of less than or equalto about 0.75±0.05. In certain embodiments, crystalline(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid anhydrate is generated at room temperature in an acetonitrile/watermixture having a water activity (a_(w)) of about 0.7. In certainembodiments, crystalline(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid anhydrate is generated at room temperature in an acetonitrile/watermixture having a a_(w) of about 0.6. In certain embodiments, crystalline(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid anhydrate is generated at room temperature in an acetonitrile/watermixture having a a_(w) of about 0.5. In certain embodiments, crystalline(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid anhydrate is generated at room temperature in an acetonitrile/watermixture having a a_(w) of about 0.4. In certain embodiments, crystalline(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid anhydrate is generated at room temperature in an acetonitrile/watermixture having a a_(w) of about 0.3. In certain embodiments, crystalline(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid anhydrate is generated at room temperature in an acetonitrile/watermixture having a a_(w) selected from about 0.7, about 0.6, about 0.5,about 0.4 and about 0.3.

In certain embodiments, crystalline(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid anhydrate undergoes thermal decomposition at a temperature rangingfrom about 170° C. to about 190° C. using a thermogravimetric analyzer(TG) coupled with a Fourier-transform infrared (FTIR) spectrometer at ascan rate of about 10 K/min.

In certain embodiments, crystalline(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid anhydrate undergoes a melt/phase transition at a temperatureranging from about 120° C. to about 140° C. using differential scanningcalorimetry at a heating rate of 20 K/min. In certain embodiments, themelt/phase transition occurs at about 131° C. and in certain embodimentsat about 131.3° C.

In certain embodiments, crystalline(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid anhydrate is not hygroscopic. In certain embodiments, crystalline(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid anhydrate contains less than about 0.05 wt % water at 50% relativehumidity as measured by dynamic vapor sorption. In certain embodiments,crystalline(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid anhydrate contains less than about 0.1 wt % water at 95% relativehumidity as measured by dynamic vapor sorption.

Methods of Synthesis

In certain embodiments, crystalline(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid anhydrate can be synthesized by: (i) forming a solution ofdiastereomers comprising(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid and(3R)-4-{[(1R)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid; (ii) selectively crystallizing the(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid diastereomer as a hemihydrate; and (iii) separating the crystalline(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid hemihydrate diastereomer from the solution. In certain embodiments,the solution is water-containing or aqueous.

In certain embodiments, crystalline(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid hemihydrate can be converted into crystalline(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid anhydrate by a method selected from drying and recrystallization.

Crystalline(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid hemihydrate (1b) can be synthesized following the methods describedin Scheme 1 and Scheme 2 below. Additionally, the individualdiastereomers of crystalline(3R)-4-{[(±)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid can be separated efficiently via the methods described in Scheme 1.Crystalline(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid anhydrate (1a) can be synthesized following the methods describedin Scheme 3 and Scheme 4 below.

In certain embodiments, crystalline(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid hemihydrate (1b) can be prepared by steps comprising providing asolution or suspension comprising1-((2,5-dioxopyrrolidin-1-yl-oxycarbonyloxy)-2-methylpropyl)-2-methylpropanoate(3) prepared as a racemic mixture of(R)-1-((2,5-dioxopyrrolidin-1-yl-oxycarbonyloxy)-2-methylpropyl)-2-methylpropanoateand(S)-1-((2,5-dioxopyrrolidin-1-yl-oxycarbonyloxy)-2-methylpropyl)-2-methylpropanoate,(R)-baclofen (2), water and a solvent; and adjusting the temperature ofthe solution or suspension to provide(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid hemihydrate (1b) and(3R)-4-{[(1R)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid (4).

In certain embodiments, the solvent is selected from methyl tert-butylether, acetonitrile, toluene, chlorobenzene, methylcyclohexane, heptane,methanol, ethanol, diethyl ether, tetrahydrofuran, tert-amyl methylether and combinations of the foregoing. In certain embodiments, thesolvent is methyl tert-butyl ether. In certain embodiments, the solventis not dimethylsulfoxide, dimethylformamide, or n-methylpyrrolidine. Incertain embodiments, the solution is aqueous. In the exemplaryembodiment depicted in Scheme 1, the solvent is methyl tert-butyl ether.

In certain embodiments, the solution comprises solvent in an amountranging from about 20 v/v %-about 50 v/v %. In certain embodiments, thesolution comprises solvent in an amount of about 35 v/v %. In theexemplary embodiment depicted in Scheme 1, the solution comprises methyltert-butyl ether in an amount of about 35 v/v %. In certain embodiments,the solution comprises water in an amount ranging from about 50 v/v % toabout 80 v/v %. In certain embodiments, the solution comprises water inan amount of about 65 v/v %. In certain embodiments, the solutioncomprises about 35 v/v % methyl tert-butyl ether and about 65% v/vwater.

In certain embodiments, the combination and dissolution of1-((2,5-dioxopyrrolidin-1-yl-oxycarbonyloxy)-2-methylpropyl)-2-methylpropanoate(3) prepared as a racemic mixture of(R)-1-((2,5-dioxopyrrolidin-1-yl-oxycarbonyloxy)-2-methylpropyl)-2-methylpropanoateand(S)-1-((2,5-dioxopyrrolidin-1-yl-oxycarbonyloxy)-2-methylpropyl)-2-methylpropanoate,and (R)-baclofen (2) in solution can be carried out at elevatedtemperature, up to and including the boiling point of the solvent used.Accordingly, in certain embodiments, racemic1-((2,5-dioxopyrrolidin-1-yl-oxycarbonyloxy)-2-methylpropyl-2-methylpropanoate(3) and (R)-baclofen (2) can be dissolved in a solution with heating andoptionally, with shaking and stirring. The heated solution may bemaintained at elevated temperature to ensure complete dissolution ofracemic1-((2,5-dioxopyrrolidin-1-yl-oxycarbonyloxy)-2-methylpropyl-2-methylpropanoate(3) and (R)-baclofen (2). The heated solution may also be filtered atelevated temperature to remove any undissolved components. Then racemic1-((2,5-dioxopyrrolidin-1-yl-oxycarbonyloxy)-2-methylpropyl-2-methylpropanoate(3) and (R)-baclofen (2) react in the solution to yield(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid (1) and(3R)-4-{[(1R)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid (4).

(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid hemihydrate can then be crystallized out of solution leaving(3R)-4-{[(1R)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid (4) in solution. Crystallization of(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid hemihydrate can occur by any number of conventional means and/or bythe methods disclosed hereinbelow.

In certain embodiments, (R)-baclofen can be recycled from diastereomer(3R)-4-{[(1R)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid (4) by hydrolysis of the(3R)-4-{[(1R)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid (4) remaining in solution according to Scheme 2.

In Scheme 2, the hydrolysis of(3R)-4-{[(1R)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid (4) yields (R)-baclofen (2), isobutyric acid (5), isobutyraldehyde(6), and carbon dioxide. The recycled (R)-baclofen (2) can then bereused in further syntheses of crystalline(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid hemihydrate (1b) via the method of Scheme 1.

Hydrolysis can occur in one or two steps. In certain embodiments, thehydrolysis of(3R)-4-{[(1R)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid (4) is achieved by adding a first solution comprising an acid andwater to the resultant crystallization solution from Scheme 1; andthereafter adding a base.

Crystalline(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid anhydrate (1a) can be synthesized following the methods describedin Scheme 3 and Scheme 4 below.

In Scheme 3, crystalline(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid hemihydrate (1b) is dried to produce crystalline(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid anhydrate (1a). Crystalline(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid hemihydrate (1b) may be produced, for example, according to themethods described above.

Drying can occur via any conventional means including, for example, airdrying, drying under vacuum, drying at an elevated temperature, or anycombination of the foregoing. In certain embodiments, the drying can becarried out at elevated temperature, up to but excluding the melting orthermal decomposition temperature of crystalline(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid anhydrate (1a). In some embodiments, the drying can be carried outat a temperature range of about 30° C. to below about 90° C., and incertain embodiments at a temperature range of about 40° C. to 80° C. Inthe exemplary embodiment depicted in Scheme 3, the drying occurs at atemperature of about 70° C.

The drying of crystalline(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid hemihydrate (1b) yields crystalline(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid anhydrate (1a) as a white crystalline solid.

In certain embodiments, crystalline(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid hemihydrate (1b) can be recrystallized to crystallize(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid anhydrate (1a).

In certain embodiments, crystalline(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid anhydrate (1a) can be prepared by steps comprising providing asolution or suspension comprising crystalline(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid hemihydrate (1b) and a solvent; and adjusting the temperature ofthe solution or suspension to provide crystalline(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid anhydrate (1a).

In certain embodiments, the solvent is selected from acetone, hexane,methyl tert-butyl ether, acetonitrile, toluene, chlorobenzene,methylcyclohexane, heptane, methanol, ethanol, diethyl ether,tetrahydrofuran, tert-amyl methyl ether and combinations of theforegoing. In certain embodiments, the solvent is a combination ofacetone and hexane. In the exemplary embodiment depicted in Scheme 1,the solvent is a combination of acetone and hexane.

In certain embodiments, the solution comprises solvent in an amountranging from about 70 v/v %-about 100 v/v %. In certain embodiments, thesolution comprises solvent in an amount of about 90 v/v %. In theexemplary embodiment depicted in Scheme 1, the solution comprises acombination of acetone and hexane in an amount of about 90 v/v %. Incertain embodiments, the solution comprises water in an amount rangingfrom about 0 v/v % to about 30 v/v %. In certain embodiments, thesolution comprises water in an amount of about 15 v/v %. In certainembodiments, the solution comprises about 90 v/v % of a combination ofacetone and hexane and about 10% v/v water.

In certain embodiments, crystalline(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid hemihydrate (1b) can be maintained at ambient or room temperatureto crystallize(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid anhydrate (1a). Ambient or room temperature refers to a temperatureto which humans are accustomed or have become acclimatized. In certainembodiments, room temperature includes temperatures in the range ofabout 20° C.-27° C. and/or temperatures in the range of about 68° F.-80°F. In certain embodiments, room temperature is 20° C., in certainembodiments 25° C., in certain embodiments 68° F., and in certainembodiments 77° F. Other methods known to those of skill in thecrystallization arts, (e.g., solvent evaporation, drowning, chemicalreaction, seeding with a small quantity of the desired crystal form,etc.) may also be employed to crystallize(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid anhydrate (1a).

In certain embodiments, the recrystallization of(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid anhydrate (1a) from a solution comprising crystalline(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid hemihydrate (1b) and a solvent can be carried out at elevatedtemperature, up to and including the boiling point of the solvent used.Accordingly, in certain embodiments, crystalline(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid hemihydrate (1b) can be dissolved in a solvent by heating andoptionally, with shaking and stirring. The heated solution may bemaintained at elevated temperature to ensure complete dissolution ofcrystalline(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid hemihydrate (1b). The heated solution may also be filtered atelevated temperature to remove any undissolved components. Then(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid anhydrate (1a) crystallizes out of the solution.

The recrystallization of crystalline(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid hemihydrate (1b) yields crystalline(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid anhydrate (1a) as a white crystalline solid.

Crystallization of(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid hemihydrate

In certain embodiments, the solution comprising1-((2,5-dioxopyrrolidin-1-yl-oxycarbonyloxy)-2-methylpropyl)-2-methylpropanoate(3) prepared as a racemic mixture of(R)-1-((2,5-dioxopyrrolidin-1-yl-oxycarbonyloxy)-2-methylpropyl)-2-methylpropanoateand(S)-1-((2,5-dioxopyrrolidin-1-yl-oxycarbonyloxy)-2-methylpropyl)-2-methylpropanoate,and (R)-baclofen (2) can be slowly cooled to crystallize(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid hemihydrate (1b). Compound (1b) may be separated from(3R)-4-{[(1R)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid (4) and residual solvent by filtration and/or drying under reducedpressure. In certain embodiments, the solution can be cooled to atemperature ranging from about 0° C. to about 25° C. to crystallize(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid hemihydrate (1b).

In certain embodiments, the solution comprising racemic1-((2,5-dioxopyrrolidin-1-yl-oxycarbonyloxy)-2-methylpropyl-2-methylpropanoate(3) and (R)-baclofen (2) can be maintained at ambient or roomtemperature to crystallize(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid hemihydrate (1b), which may be separated from(3R)-4-{[(1R)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid (4) and residual solvent by filtration and/or drying under reducedpressure. Ambient or room temperature refers to a temperature to whichhumans are accustomed or have become acclimatized. In certainembodiments, room temperature includes temperatures in the range ofabout 20° C.-27° C. and/or temperatures in the range of about 68° F.-80°F. In certain embodiments, room temperature is 20° C., in certainembodiments 25° C., in certain embodiments 68° F., and in certainembodiments 77° F. Other methods known to those of skill in thecrystallization arts, (e.g., solvent evaporation, drowning, chemicalreaction, seeding with a small quantity of the desired crystal form,etc.) may also be employed to crystallize3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid hemihydrate (1b).

Crystallization of(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid hemihydrate (1b) from the solution affords crystalline(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid hemihydrate (1b) as a white crystalline solid.

In certain embodiments, crystalline(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid hemihydrate (1b) can be prepared by steps comprising providing asolution comprising1-((2,5-dioxopyrrolidin-1-yl-oxycarbonyloxy)-2-methylpropyl-2-methylpropanoate(3) prepared as a racemic mixture, (R)-baclofen (2), water and methyltert-butyl ether; and adjusting the temperature of the solution toprovide crystalline(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid hemihydrate (1b) and(3R)-4-{[(1R)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid (4).

In certain embodiments, crystalline(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid hemihydrate (1b) can be prepared by steps comprising providing asolution comprising1-((2,5-dioxopyrrolidin-1-yl-oxycarbonyloxy)-2-methylpropyl-2-methylpropanoate(3) prepared as a racemic mixture, (R)-baclofen (2), about 65% v/v waterand about 35% v/v methyl tert-butyl ether; and adjusting the temperatureof the solution to provide crystalline(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid hemihydrate (1b) and(3R)-4-{[(1R)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid (4).

In certain embodiments, crystalline(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid hemihydrate (1b) can be prepared by steps comprising providing afirst solution comprising1-((2,5-dioxopyrrolidin-1-yl-oxycarbonyloxy)-2-methylpropyl-2-methylpropanoate(3) prepared as a racemic mixture, (R)-baclofen (2), about 65% v/v waterand about 35% v/v methyl tert-butyl ether; increasing the temperature ofthe first solution to create a second solution comprising(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid (1) and(3R)-4-{[(1R)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid (4); and decreasing the temperature of the second solution toprovide crystalline(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid hemihydrate (1b) and(3R)-4-{[(1R)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid (4).

(3R)-4-{[(1R)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid (4) is a diastereomer of(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid. In certain embodiments, the solvent or combination of solvents isselected so that(3R)-4-{[(1R)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid (4) remains in solution during crystallization of(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid hemihydrate (1b). In this way, crystalline(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid hemihydrate (1b) can be readily separated from the diastereomer(3R)-4-{[(1R)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid (4) in a single crystallization step. Other methods known to thoseof skill in the crystallization arts, (e.g., high performance liquidchromatography, reverse-phase high performance liquid chromatography,extraction, distillation extraction, chromatography, the use ofimmobilized sorbents, etc.) may also be employed to separate crystalline(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid hemihydrate (1b) from the diastereomer(3R)-4-{[(1R)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid (4).

As used herein, the terms solution and suspension are usedinterchangeably and are meant to include embodiments in which a compoundis in a solvent or solvent mixture regardless of solubility. A solventcombination can be such that a compound in solution exhibitstemperature-dependent solubility. In general, solvent combinations inwhich a compound is soluble within a first temperature range, and poorlysoluble within a second temperature range, can be used in thecrystallization methods disclosed herein. Mixtures of a “good” solventand an “anti-solvent” can also be used with temperature dependentsolubilization, i.e., dissolving at elevated temperature andcrystallizing at room temperature. Examples of suitable “good” solvents,i.e., solvents in which(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid is soluble, include methanol, ethanol, isopropanol, acetone, methylisobutyl ketone, tetrahydrofuran, 2-methyl tetrahydrofuran, 1,4-dioxane,1,2-ethandiol, 1,2-propanediol, 2-methoxyethanol, 2-ethoxyethanol, and amixture of any of the foregoing. Examples of suitable “anti-solvents”,i.e., solvents in which(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid exhibits poor solubility, include water, diethyl ether, diisopropylether, methyl t-butyl ether, toluene, chlorobenzene, alkanes such aspentane, hexane, heptane, octane, nonane, decane, undecane, dodecane,cis- or trans-decalin, cyclohexane, methylcyclohexane, and a mixture ofany of the foregoing.

Therapeutic Uses

The high (R)-baclofen oral bioavailability following administration ofcompound (1) favors the efficacious use of compound (1) in oral dosageforms, including sustained-release oral dosage forms, and the use ofsuch oral dosage forms for treating diseases such as spasticity andgastro-esophageal reflux disease (van Herwaarden et al., Aliment.Pharmacol. Ther. 2002, 16(9), 1655-62; Ciccaglione and Marzio, Gut 2003,52(4), 464-70; Andrews et al., U.S. Pat. No. 6,117,908; and Fara et al.,International Publication No. WO 02/096404); in promoting alcoholabstinence in alcoholics (Gessa et al., International Publication No. WO01/26638); in promoting smoking cessation (Gessa et al., InternationalPublication No. WO 01/08675); in reducing addiction liability ofnarcotic agents (Robson et al., U.S. Pat. No. 4,126,684); in thetreatment of emesis (Bountra et al., U.S. Pat. No. 5,719,185); as ananti-tussive for the treatment of cough (Kreutner et al., U.S. Pat. No.5,006,560); as well as for treating movement disorders such as dystoniaand hiccups; peripheral nerve disorders such as muscle stimulationdisorders; spinal cord disorders such as spastic paraparesis; cranialnerve disorders such as glossopharyngeal neuralgia and trigeminalneuralgia; multiple sclerosis; and cerebral palsy.

The pharmacological activity of (R)-baclofen,(R)-4-amino-3-(4-chlorophenyl)butanoic acid, is believed to be effectedthrough selective activation of GABA_(B) receptors, resulting inneuronal hyperpolarization. GABA_(B) receptors are located in laminaeI-IV of the spinal cord, where primary sensory fibers end. GABA_(B)receptors are G-protein coupled receptors that activate conductance byK⁺-selective ion channels and can reduce currents mediated by Ca²⁺channels in certain neurons. Baclofen has a pre-synaptic inhibitoryeffect on the release of excitatory neurotransmitters and also actspostsynaptically to decrease motor neuron firing (see Bowery, TrendsPharmacol. Sci. 1989, 10, 401-407; and Misgeld et al., Prog. Neurobiol.1995, 46, 423-462).

A principal pharmacological effect of baclofen in mammals is reductionof muscle tone and consequently the drug is frequently used in thetreatment of spasticity. Spasticity is associated with damage to thecorticospinal tract and is a common complication of neurologicaldisease. Diseases and conditions in which spasticity may be a prominentsymptom include cerebral palsy, multiple sclerosis, stroke, head andspinal cord injuries, traumatic brain injury, anoxia, andneurodegenerative diseases. Patients with spasticity complain ofstiffness, involuntary spasm, and pain. These painful spasms may bespontaneous or triggered by a minor sensory stimulus, such as touchingthe patient.

Baclofen is also useful in controlling gastro-esophageal reflux disease(van Herwaarden et al., Aliment. Pharmacol. Ther. 2002, 16(9), 1655-62;Ciccaglione and Marzio, Gut 2003, 52(4), 464-70; Andrews et al., U.S.Pat. No. 6,117,908; and Fara et al., International Publication No. WO02/096404); in promoting alcohol abstinence in alcoholics (Gessa et al.,International Publication No. WO 01/26638); in promoting smokingcessation (Gessa et al., International Publication No. WO 01/08675); inreducing addiction liability of narcotic agents (Robson et al., U.S.Pat. No. 4,126,684); in the treatment of emesis (Bountra et al., U.S.Pat. No. 5,719,185); as an anti-tussive for the treatment of cough(Kreutner et al., U.S. Pat. No. 5,006,560); in treating neuropathic pain(see e.g., Fromm et al., Neurology 1981, 31(6), 683-7; and Ringel andRoy, Ann Neurol 1987, 21(5), 514-5); and in treating musculoskeletalpain (see e.g., Hering-Hanit, Cephalalgia 1999, 19(6), 589-591;Hering-Hanit and Gadoth, Headache 2000, 40(1), 48-51; Freitag, CNS Drugs2003, 17(6), 373-81; Slonimski et al., Reg Anesth Pain Med 2004, 29(3),269-76).

Accordingly, administering crystalline(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid anhydrate and/or crystalline(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid hemihydrate, both of which are the (R)-baclofen prodrugs, to apatient can be expected to be useful in treating diseases and disordersassociated with the GABA_(B) receptor and/or any of the diseases anddisorders (R)-baclofen is known to treat.

The suitability of the (R)-baclofen prodrugs crystalline(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid anhydrate and/or crystalline(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid hemihydrate in treating the above-listed diseases may be determinedby methods described in the art (see, e.g., Bowery, Trends Pharmacol.Sci. 1989, 10, 401-407; Misgeld et al., Prog. Neurobiol. 1995, 46,423-462; van Herwaarden et al., Aliment. Pharmacol. Ther. 2002, 16(9),1655-62; Ciccaglione and Marzio, Gut 2003, 52(4), 464-470; Andrews etal., U.S. Pat. No. 6,117,908; Fara et al., International Publication No.WO 02/096404; Gessa et al., International Publication No. WO 01/26638;Gessa et al., International Publication No. WO 01/08675); Robson et al.,U.S. Pat. No. 4,126,684; Bountra et al., U.S. Pat. No. 5,719,185; andKreutner et al., U.S. Pat. No. 5,006,560; Katz, Am. J. Phys. Med.Rehabil. 1988, 67(3), 108-16; Krach, J. Child Neurol. 2001, 16(1), 31-6;Bryans et al., International Publication No. WO 01/90052; Bryans et al.,EP 1178034; Cundy et al., U.S. Application Publication No. 2002/0151529;Gallop et al., U.S. Application Publication No. 2003/0176398; Gallop etal., U.S. Application Publication No. 2003/0171303; Gallop et al., U.S.Application Publication No. 2004/0006132; and Raillard et al., U.S.Application Publication No. 2004/0014940).

A suitable dose of crystalline(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid anhydrate and/or a suitable dose of crystalline(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid hemihydrate to be administered to a patient in need of (R)-baclofentherapy may be estimated based on the mass equivalent of (R)-baclofenand the enhanced oral bioavailability of (R)-baclofen provided bycrystalline(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid anhydrate and/or crystalline(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid hemihydrate.

In various aspects, crystalline(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid anhydrate and/or crystalline(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid hemihydrate, or pharmaceutical compositions comprising either ofcrystalline(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid anhydrate and/or crystalline(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid hemihydrate, may be administered to a patient, such as a human,suffering from treating a disease or disorder chosen from spasticity,gastroesophageal reflux disease, emesis, cough, substance addiction andabuse, neuropathic pain and musculoskeletal pain.

Further, in certain embodiments, crystalline(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid anhydrate and/or crystalline(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid hemihydrate, or pharmaceutical compositions comprising crystalline(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid anhydrate and/or crystalline(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid hemihydrate, can be administered to a patient, such as a human, asa preventative measure against various diseases or disorders.Crystalline(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid anhydrate and/or crystalline(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid hemihydrate, or pharmaceutical compositions comprising crystalline(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid anhydrate and/or crystalline(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid hemihydrate, may be administered as a preventative measure to apatient having a predisposition for spasticity, gastroesophageal refluxdisease, emesis, cough, substance addiction and abuse, neuropathic painand musculoskeletal pain. Accordingly, crystalline(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid anhydrate and/or crystalline(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid hemihydrate, or pharmaceutical compositions comprising crystalline(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid anhydrate and/or crystalline(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid hemihydrate, may be used for the prevention of one disease ordisorder and concurrently for the treatment of another (e.g., preventionof spasticity while treating a narcotic addiction; prevention ofneuropathic pain while treating gastroesophageal reflux disease).

Both crystalline(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid anhydrate and crystalline(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid hemihydrate may be more efficacious than the parent drug molecule(i.e. baclofen) in treating spasticity, gastroesophageal reflux disease,emesis, cough, substance addiction and abuse, neuropathic pain andmusculoskeletal pain because, when administered orally, the compoundprovides for sustained therapeutically effective blood concentrations of(±)-4-amino-3-(4-chlorophenyl)butanoic acid. It is believed thatmetabolites of both crystalline(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid anhydrate and crystalline(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid hemihydrate are absorbed from the gastrointestinal lumen into theblood by a different mechanism than that by which baclofen and otherknown GABA analogs are absorbed. For example, pregabalin is believed tobe actively transported across the gut wall by a carrier transporterlocalized in the human small intestine. In contrast, the compoundsdisclosed herein, and/or metabolites thereof are believed to be absorbedacross the gut wall along a greater portion of the gastrointestinaltract, including the colon.

Because metabolites of both crystalline(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid anhydrate and crystalline(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid hemihydrate can be absorbed throughout the gastrointestinal tract,including the colon, both compounds can be advantageously formulated insustained release oral formulations that provide for sustained releaseof one or both of the compounds over a period of hours into thegastrointestinal tract. The ability of both crystalline(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid anhydrate and crystalline(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid hemihydrate to be used in sustained release oral dosage forms canfacilitate therapeutic regimens having a reduced dosing frequencynecessary to maintain a therapeutically effective baclofen concentrationin the blood.

In certain embodiments, crystalline(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid anhydrate, crystalline(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid hemihydrate, combinations thereof, and/or pharmaceuticalcompositions thereof, can be administered to a patient for treating adisease or disorder selected from spasticity, gastroesophageal refluxdisease, emesis, cough, substance addiction and abuse, neuropathic painand musculoskeletal pain.

Spasticity

In certain embodiments, crystalline(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid anhydrate can be administered to a patient to treat spasticity. Incertain embodiments, crystalline(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid hemihydrate can be administered to a patient to treat spasticity.

Spasticity is estimated to affect about 500,000 people in the UnitedStates and more than 12 million people worldwide. Spasticity is aninvoluntary, velocity-dependent, increased resistance to stretch.Spasticity is characterized by muscle hypertonia in which there isincreased resistance to externally imposed movement with increasingspeed of stretch (Lance et al., Trans Am. Neurol. Assoc. 1970, 95,272-274; and Sanger et al., Pediatrics 2003, 111, e89-e97). Spasticitycan be caused by lack of oxygen to the brain before, during, or afterbirth (cerebral palsy); physical trauma (brain or spinal cord injury);blockage of or bleeding from a blood vessel in the brain (stroke);certain metabolic diseases; adrenolekodystrophy; phenylketonuria;neurodegenerative diseases such as Parkinson's disease and amyotrophiclateral sclerosis; and neurological disorders such as multiplesclerosis. Spasticity is associated with damage to the corticospinaltract and is a common complication of neurological disease. Diseases andconditions in which spasticity may be a prominent symptom includecerebral palsy, multiple sclerosis, stroke, head and spinal cordinjuries, traumatic brain injury, anoxia, and neurodegenerativediseases. Patients with spasticity complain of stiffness, involuntaryspasm, and pain. These painful spasms may be spontaneous or triggered bya minor sensory stimulus, such as touching the patient.

Symptoms of spasticity can include hypertonia (increased muscle tone),clonus (a series of rapid muscle contractions), exaggerated deep tendonreflexes, muscle spasms, scissoring (involuntary crossing of the legs),deformities with fixed joints, stiffness, and/or fatigue caused bytrying to force the limbs to move normally. Other complications includeurinary tract infections, chronic constipation, fever or other systemicillnesses, and/or pressure sores. The degree of spasticity can vary frommild muscle stiffness to severe, painful, and uncontrollable musclespasms. Spasticity may coexist with other conditions but isdistinguished from rigidity (involuntary bidirectionalnon-velocity-dependent resistance to movement), clonus (self-sustainingoscillating movements secondary to hypertonicity), dystonia (involuntarysustained contractions resulting in twisting abnormal postures),athetoid movement (involuntary irregular confluent writhing movements),chorea (involuntary, abrupt, rapid, irregular, and unsustainedmovements), ballisms (involuntary flinging movements of the limbs orbody), and tremor (involuntary rhythmic repetitive oscillations, notself-sustaining). Spasticity can lead to orthopedic deformity such aship dislocation, contractures, or scoliosis; impairment of daily livingactivities such as dressing, bathing, and toileting; impairment ofmobility such as inability to walk, roll, or sit; skin breakdownsecondary to positioning difficulties and shearing pressure; pain orabnormal sensory feedback; poor weight gain secondary to high caloricexpenditure; sleep disturbance; and/or depression that is secondary tolack of functional independence.

Treatment of spasticity includes physical and occupational therapy suchas functional based therapies, rehabilitation, facilitation such asneurodevelopmental therapy, proprioceptive neuromuscular facilitation,and sensory integration; biofeedback: electrical stimulation; andorthoses. Oral medications useful in treating spasticity includebaclofen, benzodiazepines such as diazepam, dantrolene sodium;imidazolines such as clonidine and tizanidine; and gabapentin.Intrathecal medications useful in treating spasticity include baclofen.Chemodenervation with local anesthetics such as lidocaine and xylocalne;type A botulinum toxin and type B botulinum toxin; phenol and alcoholinjection can also be useful in treating spasticity. Surgical treatmentsuseful in treating spasticity include neurosurgery such as selectivedorsal rhizotomy; and orthopedic operations such as contracture release,tendon or muscle lengthening, tendon transfer, osteotomy, andarthrodesis.

The efficacy of crystalline(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid anhydrate and/or crystalline(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid hemihydrate for the treatment of spasticity can be assessed usinganimal models of spasticity and in clinically relevant studies ofspasticity of different etiologies. Animal models of spasticity areknown (see e.g., Eaton, J Rehab Res Dev 2003, 40(4), 41-54; Kakinohanaet al., Neuroscience 2006, 141, 1569-1583; Ligresti et al., British JPharm 2006, 147, 83-91; Zhang et al., Chinese J Clin Rehab, 2006,10(38), 150-151; Hefferan et al., Neuroscience Letters 2006, 403,195-200; and Li et al., J Neurophysiol 2004, 92, 2694-2703). Forexample, animal models of spasticity include: (a) the mutant spasticmouse (Chai et al., Proc. Soc. Exptl. Biol. Med. 1962, 109, 491); (b)the acute/chronic spinally transected rat and the acute decerebrate rat(see e.g., Wright and Rang, Clin Orthop Relat Res 1990, 253, 12-19;Shimizu et al., J Pharmacol Sci 2004, 96, 444-449; and Li et al., JNeurophysiol 2004, 92, 2694-2703); (c) primary observation Irwin Test inthe rat (Irwin, Psychopharmacologia 1968, 13, 222-57); and d) RotarodTest in the rat and mouse (Dunham et al., J. Am. Pharm. Assoc. 1957, 46,208-09). Other animal models include spasticity induced in ratsfollowing transient spinal cord ischemia (Kakinohana et al.,Neuroscience 2006, 141, 1569-1583; and Hefferan et al., NeuroscienceLetters 2006, 403, 195-200), spasticity in mouse models of multiplesclerosis (Ligresti et al., British J Pharmacol 2006, 147, 83-91); andspasticity in rat models of cerebral palsy (Zhang et al., Chinese J ClinRehabilitation 2006, 10(38), 150-151). The maximal electroshock seizure(MES) threshold test in rodents is sensitive for detecting potentialanticonvulsant properties (Loscher and Schmidt, Epilepsy Res 1988, 2(3),145-181). In this model, anticonvulsant agents elevate the threshold toelectrically-induced seizures while proconvulsants lower the seizurethreshold.

The efficacy of crystalline(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid anhydrate and/or crystalline(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid hemihydrate for treating spasticity may also be assessed in humansusing double blind placebo-controlled clinical trials (see e.g., Priebeet al., Spinal Cord 1997, 35(3), 171-5; Gruenthal et al., Spinal Cord1997, 35(10), 686-9; Tuszynski et al., Spinal Cord 2007, 45, 222-231 andSteeves et al., Spinal Cord 2007, 45, 206-221 for examples of theconduct and assessment of clinical trials for spasticity caused byspinal cord injury). Clinical trial outcome measures for spasticityinclude the Ashworth Scale, the modified Ashworth Scale, muscle stretchreflexes, presence of clonus and reflex response to noxious stimuli.Spasticity can be assessed using methods and procedures known in the artsuch as a combination of clinical examination, rating scales such as theAshworth Scale, the modified Ashworth scale the spasm frequency scaleand the reflex score, biomechanical studies such as the pendulum test,electrophysiologic studies including electromyography, and functionalmeasurements such as the Fugl-Meyer Assessment of SensorimotorImpairment scale. Other measures can be used to assess spasticityassociated with a specific disorder such as the Multiple SclerosisSpasticity Scale (Hobart et al., Brain 2006, 129(1), 224-234).

Gastroesophageal Reflux Disease

In certain embodiments, crystalline(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid anhydrate can be administered to a patient to treatgastroesophageal reflux disease. In certain embodiments, crystalline(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid hemihydrate can be administered to a patient to treatgastroesophageal reflux disease.

Gastroesophageal reflux disease (GERD) is defined as chronic symptoms ormucosal damage produced by abnormal reflux in the esophagus. Symptoms ofGERD include heartburn, esophagitis, stictures, dysphagia, chronic chestpain, cough, hoarsness, voice changes, chronic ear ache, burning chestpains, nausea, and sinusitis.

Tonic contraction of the lower esophageal sphincter is the principalfactor preventing the reflux of gastric contents into the esophagus.Transient lower esophageal sphincter relaxation (TLESR) is the majormechanism underlying reflux in normal subjects and patients with GERD.GABA_(B) agonists such as R-baclofen have been shown to reduce TLESRs inhumans (Lidums et al., Gastroenterology 2000, 118(1), 7-13; Vela et al.,Aliment Pharmacol Ther 2003, 17(2), 243-51; Ciccaglione and Marzio, Gut2003, 52(4), 464-70; and Zhang et al., Gut 2002, 50(1), 19-24).Reduction of the frequency of TLESRs by baclofen is believed to be dueto inhibition of vagal afferents, information transfer between thenucleus tractus solitarious and dorsal motor nucleus of the vagus, andvagal efferent outflow (Hornby et al., Gastroenterol Clin N Am 2002,31(4 Suppl), S11-S20).

More specifically,(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid (1) has been shown to reduce reflux episodes in clinical trials(Castell et al., Am J. Gastroenterology 2006, 101(suppl 2)(52), S59 andposter presentation at American College of Gastroenterology 2006 AnnualMeeting, Oct. 20-25, 2006, Las Vegas, Nev.; and Castell et al.,Gastroenterology 2007, suppl. A, 486 and poster presentation atDigestive Disease Week Meeting, May 19-24, 2007, Washington D.C.).

The efficacy of crystalline(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid anhydrate and/or crystalline(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid hemihydrate for treating GERD may be assessed using animal modelssuch as those described by Blackshaw et al., Am. J. Physiol. 1999, 277,G867-G874; Lehmann et al., Gastroenterology 1999, 117, 1147-1154; andStakeberg and Lehmann, Neurogastroenterol. Mot. 1999, 11, 125-132; andin clinical trials.

Emesis

In certain embodiments, crystalline(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid anhydrate can be administered to a patient to treat emesis. Incertain embodiments, crystalline(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid hemihydrate can be administered to a patient to treat emesis.

Nausea, vomiting, and retching are basic human protective reflexesagainst the absorption of toxins as well as responses to certainstimuli. Nausea is a subjectively unpleasant wavelike sensation in theback of the throat or epigastrium associated with pallor or flushing,tachycardia, and an awareness of the urge to vomit. Sweating, excesssalivation, and a sensation of being cold or hot may also occur.Vomiting is characterized by contraction of the abdominal muscles,descent of the diaphragm, and opening of the gastric cardia, resultingin forceful expulsion of stomach contents from the mouth. Retchinginvolves spasmodic contractions of the diaphragm and the muscles of thethorax and abdominal wall without expulsion of gastric contents. Emesisis used herein to refer to nausea, vomiting, and/or retching.

Baclofen has been shown to suppress the retching and vomiting induced bymorphine, thereby indicating the involvement of the GABA_(B) receptor inthe emetic control pathway (Suzuki et al., Neuropharmacology 2005,49(8), 1121-31). Baclofen has also been shown to antagonize emesisinduced by nicotine and motion in animal models (Chan et al., Eur JPharmacology 2007, 559(2-3), 196-201).

The efficacy of crystalline(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid anhydrate and/or crystalline(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid hemihydrate for treating emesis can be assessed using appropriateanimal models and using clinical trials. For example, efficacy intreating emesis induced by chemotherapeutic agents can be determinedbased on effects indicative of emesis such as pica, gastric stasis, andreduced food intake in rats, mice, or ferrets (see, e.g., Liu et al.,Physiology & Behavior, 2005, 85, 271-277; Endo et al., Biogenic Amines,2004, 18(3-6), 419-434; and Malik et al., Eur. J. Pharmacol, 2007, 555,164-173). In clinical trials, assessment instruments such as the DukeDescriptive Scale, Visual Analog Scales, Morrow Assessment of Nausea andEmesis, Rhodes Index of Nausea and Vomiting Form-2, and FunctionalLiving Index Emesis can be used to measure efficacy (see, e.g., Rhodeset al., CA Cancer J Clin, 2001, 51, 232-248 and references therein). Ingeneral, adequately controlled, double blind placebo controlled trailsmay be used to evaluate efficacy in humans.

Cough

In certain embodiments, crystalline(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid anhydrate can be administered to a patient to treat cough. Incertain embodiments, crystalline(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid hemihydrate can be administered to a patient to treat cough.

Cough reflex, elicited by activation of cough receptors located in therespiratory tract, clears inhaled irritants and foreign substances fromthe respiratory tract and, in conjunction with the mucociliary system,can expel excessive airway secretion produced under abnormal conditionsfrom the respiratory tract. Cough can be caused by mild acuate upperrespiratory tract infections, allergies, asthma, chronic obstructivepulmonary disease, lung cancer, gastroesophageal reflux disease,post-nasal drip, and heart or ear disorders. However, chronicnon-productive cough having no identifiable cause accounts for asignificant percent of patients presenting with cough. Chronic cough isassociated with exacerbation of asthmatic symptoms, rib fractures,breathlessness, ruptured abdominal muscles, pneumothorax, syncope,second and third degree heart block, and loss of consciousness.Persistent and uncontrollable cough can lead to morbidity and severelyimpairs the quality of life of these patients.

Cough includes acute and chronic cough of any type, etiology, orpathogenesis, and in particular cough associated with laryngeal sensoryneuropathy.

The anti-tussive effects of baclofen are well-known (see e.g.,Dicpinigaitis and Dobkin, Chest 1997, 111(4), 996-9; Dicpinigaitis andRauf, Respiration 1998, 65(1), 86-8; Dicpinigaitis et al., J ClinPharmacol 1998, 38(4), 364-7; and Kreutner et al., U.S. Pat. No.5,006,560 and International Publication No. WO 91/08740).

The efficacy of crystalline(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid anhydrate and/or crystalline(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid hemihydrate for treating cough can be assessed using appropriateanimal models and using clinical trials. Animal models of cough arereviewed by Lewis et al., Pulmonary Pharmacology & Therapeutics 2007,20, 325-333.

Substance Addiction or Abuse

In certain embodiments, crystalline(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid anhydrate can be administered to a patient to treat substanceaddiction or abuse. In certain embodiments, crystalline(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid hemihydrate can be administered to a patient to treat substanceaddiction or abuse.

In clinical trials, (R)-baclofen has been shown to be effective intreating cocaine addiction (Brebner et al., Alcohol & Alcoholism 2002,37(5), 478-84; and Haney et al., Neuropsychopharmacology 2006, 31,1814-21); methamphetamine dependence (Heinzerling et al., Drug AlcoholDepend 2006, 85(3), 177-84); opioid dependence (Assadi et al., BMCPsychiatry 2003, 3(16); and Ahmadi-Abhari et al., J Clin PharmTherapeutics 2001, 26(1), 67-71); alcohol craving and intake (Addoloratoet al., Alcohol & Alcoholism 2002, 37(5), 504-8; and Flannery et al.,Alcohol Clin Exp Res 2004, 28(10), 1517-23); nicotine use (Markou etal., Ann N.Y. Acad Sci 2004, 1025, 491-503); and drug addictiongenerally (Cousins et al., Drug Alcohol Dependence 2002, 65(3), 209-20).

The efficacy of crystalline(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid anhydrate and/or crystalline(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid hemihydrate for treating substance addiction and abuse can beassessed using animal models and in clinical trials. Animal models ofsubstance abuse disorders are known (see e.g., Fattore et al., Alcohol &Alcoholism 2002, 37(5), 495-498 (nicotine); Spano et al.,Neuropharmacology 2007, 52, 1555-1562 (opiate addiction); and Maccioniet al., Alcohol 2005, 36, 161-168 (alcohol abuse)).

Neuropathic Pain

In certain embodiments, crystalline(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid anhydrate can be administered to a patient to treat neuropathicpain. In certain embodiments, crystalline(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid hemihydrate can be administered to a patient to treat neuropathicpain.

It is estimated that neuropathic pain affects over 6 million patients inthe U.S. and Europe and over 26 million patients worldwide. Neuropathicpain involves an abnormal processing of sensory input usually occurringafter direct injury or damage to nerve tissue. Neuropathic pain is acollection of disorders characterized by different etiologies includinginfection, inflammation, disease such as diabetes and multiplesclerosis, trauma or compression to major peripheral nerves, andchemical or irradiation-induced nerve damage (Jensen et al., Eur JPharmacol 2001, 429, 1-11). Neuropathic pain typically persists longafter tissue injury has resolved. Prodrugs of GABA_(B) agonists providedby the present disclosure can be used to treat neuropathic pain. Incertain embodiments, crystalline(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid anhydrate and/or crystalline(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid hemihydrate can be used to treat neuropathic pain including, forexample, post-herpetic neuralgia, peripheral neuropathy, trigeminalneuralgia, painful diabetic neuropathy, HIV-related neuropathic pain,cancer-related pain, and/or fibromyalgia.

The International Association for the Study of Neuropathic Pain definesneuropathic pain states as disorders that are characterized by lesionsor dysfunction of the neural system(s) which, under normal conditions,transmit noxious information to the central nervous system. Themechanisms underlying neuropathic pain conditions are highlyheterogeneous, however all types of neuropathic pain are presumed toinvolve nerve injury and certain common aberrations in somatosensoryprocessing in the central and/or peripheral nervous system (Baron, NatClin Pract Neurol 2006, 2, 95-106; and Beggs and Salter, Drug Dev Res2006, 67, 289-301). Potential causes of neuropathic pain includephysical damage, infection, and chemical exposure. Neuropathic pain canbe generally classified as a focal/multifocal lesion of the peripheralnervous system, e.g., post-herpetic neuralgia, a generalized lesion ofthe peripheral nervous system, painful diabetic neuropathy, HIV-relatedneuropathic pain, a lesion of the central nervous system, or a morecomplex neuropathic disorder. Peripheral neuropathic pain can arise as aconsequence of trauma and surgery related nerve injury, e.g., brachialplexus injury; entrapment neuropathies such as lumbar disc compression,carpal tunnel syndrome; disease-related neuropathies, e.g., diabetes andHIV-AIDS; radiculopathy; complex regional pain syndrome; and/or tumorgrowth leading to nerve compression or infiltration. Central neuropathicpain can be the result of stroke, multiple sclerosis, post-ischemicmyelopathy; post-herpetic neuralgia; and/or post-traumatic spinal cordinjury.

An essential part of neuropathic pain is a partial or complete loss ofafferent sensory function and the paradoxical presence of certainhyperphenomena in the painful area. The nerve tissue lesion may be foundin the brain, spinal cord, or the peripheral nervous system. Symptomsvary depending on the condition and can manifest as hyperalgesia (thelowering of pain threshold and an increased response to noxiousstimuli), allodynia (the evocation of pain by non-noxious stimuli suchas cold, warmth, or touch), hyperpathia (an explosive pain response thatis suddenly evoked from cutaneous areas with increased sensory detectionthreshold when the stimulus intensity exceeds sensory threshold),paroxysms (a type of evoked pain characterized by shooting, electric,shock-like or stabbing pain that occur spontaneously, or followingstimulation by an innocuous tactile stimulus or by a blunt pressure),paraesthesia (abnormal but non-painful sensations, which can bespontaneous or evoked, often described as pins and needles), dysesthesia(abnormal unpleasant but not necessarily painful sensation, which can bespontaneous or provoked by external stimuli), referred pain and abnormalpain radiation (abnormal spread of pain), and wind-up like pain andafter sensations (the persistence of pain long after termination of apainful stimulus).

Patients with neuropathic pain typically describe burning, lancinating,stabbing, cramping, aching, and sometimes vice-like pain. The pain canbe paroxysmal or constant. Pathological changes to the peripheralnerve(s), spinal cord, and brain have been implicated in the inductionand maintenance of chronic pain. Patients suffering from neuropathicpain typically endure chronic, debilitating episodes that are refractoryto current pharmacotherapies and profoundly affect their quality oflife. Currently available treatments for neuropathic pain, includingtricyclic antidepressants and gabapentin, typically show limitedefficacy in the majority of patients (Sindrup and Jensen, Pain 1999, 83,389-400).

There are several types of neuropathic pain. A classification thatrelates to the type of damage or related pathophysiology causing apainful neuropathy includes neuropathies associated with mechanicalnerve injury such as carpal tunnel syndrome, vertebral disk herniation,entrapment neuropathies, ulnar neuropathy, and neurogenetic thoracicoutlet syndrome; metabolic disease associated neuropathies such asdiabetic polyneuropathy; neuropathies associated with neurotropic viraldisease such as herpes zoster and human immunodeficiency virus disease;neuropathies associated with neurotoxicity such as chemotherapy ofcancer or tuberculosis, radiation therapy, drug-induced neuropathy, andalcoholic neuropathy; neuropathies associated with inflammatory and/orimmunologic mechanisms such as multiple sclerosis, anti-sulfatideantibody neuropathies, neuropathy associated with monoclonal gammopathy,Sjogren's disease, lupus, vasculitic neuropathy, polyclonal inflammatoryneuropathies, Guillain-Barre syndrome, chronic inflammatorydemyelinating neuropathy, multifocal motor neuropathy, paraneoplasticautonomic neuropathy, ganglinoic acetylcholine receptor antibodyautonomic neuropathy, Lambert-Eaton myasthenic syndrome and myastheniagravis; neuropathies associated with nervous system focal ischemia suchas thalamic syndrome (anesthesia dolorosa); neuropathies associated withmultiple neurotransmitter system dysfunction such as complex regionalpain syndrome; neuropathies associated with chronic/neuropathic painsuch as osteoarthritis, low back pain, fibromyalgia, cancer bone pain,chronic stump pain, phantom limb pain, and paraneoplastic neuropathies;toxic neuropathies (e.g., exposure to chemicals such as exposure toacrylamide, 3-chlorophene, carbamates, carbon disulfide, ethylene oxide,n-hexane, methyl n-butylketone, methyl bromide, organophosphates,polychlorinated biphenyls, pyriminil, trichlorethylene, ordichloroacetylene), focal traumatic neuropathies, phantom and stumppain, monoradiculopathy, and trigeminal neuralgia; and centralneuropathies including ischemic cerebrovascular injury (stroke),multiple sclerosis, spinal cord injury, Parkinson's disease, amyotrophiclateral sclerosis, syringomyelia, neoplasms, arachnoiditis, andpost-operative pain; mixed neuropathies such as diabetic neuropathies(including symmetric polyneuropathies such as sensory or sensorimotorpolyneuropathy, selective small-fiber polyneuropathy, and autonomicneuropathy; focal and multifocal neuropathies such as cranialneuropathy, limb mononeuropathy, trunk mononeuropathy, mononeuropathymultiplex, and asymmetric lower limb motor neuropathy) andsympathetically maintained pain. Other neuropathies include focalneuropathy; glosopharyngeal neuralgia; ischemic pain; trigeminalneuralgia; atypical facial pain associated with Fabry's disease, Celiacdisease, hereditary sensory neuropathy, or B12-deficiency;mono-neuropathies; polyneuropathies; hereditary peripheral neuropathiessuch as Carcot-Marie-Tooth disease, Refsum's disease, Strumpell-Lorraindisease, and retinitis pigmentosa; acute polyradiculoneuropathy; andchronic polyradiculoneuropathy. Paraneoplastic neuropathies includeparaneoplastic subacute sensory neuropathy, paraneoplastic motor neurondisease, paraneoplastic neuromyotonia, paraneoplastic demyelinatingneuropathies, paraneoplastic vasculitic neuropathy, and paraneoplasticautonomic insufficiency. Prodrugs of GABA_(B) agonists, such ascrystalline(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid anhydrate and/or crystalline(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid hemihydrate, can be used to treat any of the foregoing types ofneuropathic pain. In certain embodiments, the neuropathic pain is chosenfrom post-herpetic neuralgia, peripheral neuropathy, trigeminalneuralgia, painful diabetic neuropathy, HIV-related neuropathic pain,cancer-related pain, and fibromyalgia. In certain embodiments, theneuropathic pain is chosen from post-herpetic neuralgia and trigeminalneuralgia.

The GABA_(B) agonist (R)-baclofen has long been known to haveantinociceptive activity in models of acute pain and recent studies haveshown that baclofen inhibits allodynia and hyperalgesia in the chronicconstriction injury and spinal nerve ligation models of persistentneuropathic pain at doses lower than those required to produce sedationand impairment of motor activity (see e.g., Hwang and Yaksh, Pain 1997,70(1), 15-22; Smith et al., Neruopharmacology 1994, 33(9), 1103-8; Patelet al., Pain 2001, 90(3), 217-26; Balerio and Rubio, Pharmacol Res 2002,46(3), 281-6; and Reis and Duarte, Br J Pharmacol 2006, 149(6), 733-9).

In clinical studies, intrathecal baclofen administration has been shownto be effective in treating neuropathic pain associated with spinal-cordinjury and multiple sclerosis (Herman et al., Clin J Pain 1992, 8(4),338-45), painful extremity paresthesias (Gatscher et al., Acta NeurochirSuppl 2002, 79, 75-76), sympathetically maintained pain (Van Hilten etal., N Engl J Med 2000, 343(9), 625-30; Becker et al., J Clin Neurosci2000, 7(4), 316-9; and Zuniga et al., Reg Anesth Pain Med 2002, 27(1),90-3). GABA_(B) agonists such as baclofen have also been shown to beeffective in trigeminal, gloospharyngeal, vagoglossopharyngeal, andophthalmic-postherpetic neuralgias (Fromm et al., Neurology 1981, 31(6),683-7; and Ringel and Roy, Ann Neurol 1987, 21(5), 514-5); and inpatients with diabetic neuropathy (Anghinah et al., Muscle Nerve 1994,17(8), 958-59). Doses of baclofen from about 50 mg/day to about 60mg/day have been shown to be effective in treating trigeminal neuralgia(Fromm et al., Ann Neurol 1984, 15(3), 240-4).

The efficacy of crystalline(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid anhydrate and/or crystalline(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid hemihydrate for treating one or more types of neuropathic pain canbe assessed in animal models of neuropathic pain and in clinical trials(see e.g., Beggs and Salter, Drug Dev Res 2006, 67, 829-301). Usefulanimal models of neuropathic pain include peripheral nerve injury byligation or transection including dorsal rhizotomy (Lombard et al., Pain1979, 6(2), 163-174); spinal nerve ligation (Kim and Chung, Pain 1992,50, 355-363; and Hwang and Yaksh, Pain 1997, 70(1), 15-22); sciaticnerve transaction (Wall et al., Pain 1979, 7, 103-111); sciatic nervecuff (Mosconi and Kruger, Pain 1996, 64, 37-57); partial nerve ligation(Seltzer et al., Pain 1990, 43, 205-218); chronic constriction (Bennettand Xie, Pain 1988, 33, 87-107); rat spinal cord ischemia model (Hao etal., Pain 1991, 45, 175-185; and von Heijne et al., Eur J Pain 2001, 5,1-10); and spared nerve injury (Decosterd and Woolf, Pain 2000, 87,149-158). Other animal models of neuropathies involving immune systemactivation and metabolic and chemically induced neuropathies includesciatic cyroneurolysis (DeLeo et al., Pain 1994, 56, 9-16);zymosan-induced neuritis (Chacur et al., Pain 2001, 94, 231-244); HIVgp120-induced pain model (Herzberg and Sagen, J Neuroimmunol 2001, 116,29-39); photochemical ischemia (Kupers et al., Pain 1998, 76(1-2),45-59); anti-ganglioside antibody (Slart et al., Pain 1997, 69,119-125); streptozotocin-neuropathy (Fox et al., Pain 1999, 81,307-316); DDI-induced myelinopathy (Joseph et al., Pain 2004, 107,147-158); formalin phase 2 model of hyperalgesic pain (Dirig and Yaksy,J Pharmacology Exper Ther 1995, 275, 219-227); vincristine-induced painmodel (Aley et al., Neuroscience 1996, 73, 259-265); paclitaxel-inducedpain model (Cavaletti et al., Exp Neurol 1995, 133, 64-72); andcisplatin-induced pain model (Authier et al., Neurosci Lett 2000, 25,2576-2585).

The efficacy of crystalline(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid anhydrate and/or crystalline(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid hemihydrate for treating various types of neuropathic pain can alsobe assessed in clinical trials using, for example, randomizeddouble-blind placebo controlled methods. End points used in clinicaltrials for neuropathic pain can be determined using validatedneuropathic pain criteria such as the Brief Pain Inventory, CategoricalScale, Gracety Pain Scale, Likert Scale, Neuropathic Pain Scale,Numerical Pain Scale, Short Form McGill Pain Questionnaire, Verbal PainScale, Visual Analog Scale (VAS), VAS Pain Intensity Scale, and/or VASPain Relief Scale.

Musculoskeletal Pain

In certain embodiments, crystalline(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid anhydrate can be administered to a patient to treat musculoskeletalpain. In certain embodiments, crystalline(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid hemihydrate can be administered to a patient to treatmusculoskeletal pain.

Musculoskeletal conditions causing tenderness, musculosketal pain andmuscle spasms include fibromyalgia, tension headaches, myofascial painsyndrome, facet joint pain, internal disk disruption, somaticdysfunction, spinal fractures, vertebral osteomyelitis, polymyalgiarheumatica, atlantoaxial instability, atlanto-occipital joint pain,osteoporotic vertebral compression fracture, Scheuermann's disease,spondyloysis, spondylolisthesis, kissing spines, sacroiliac joint pain,sacral stress fracture, coccygodynia, failed back syndrome, andmechanical low back or neck pain (see, e.g., Meleger and Krivickas,Neurol Clin 2007, 25, 419-438. In these conditions, muscle spasm isrelated to local factors involving the affected muscle groups withoutthe increased tone or reflex characteristic of spasticity. Muscle,tendon, ligament, intervertebral disc, articular cartilage, and bone canbe involved in musculoskeletal pain. Disorders that can produce neck andback pain include muscle strain, ligament sprain, myofascial pain,fibromyalgia, facet joint pain, internal disc disruption, somaticdysfunction, spinal fracture, verterbral osteomyelitis, and polymyalgiarheumatica, atlantoaxial instability and atlanto-occipital joint pain.(see e.g., Meleger and Krivickas, Neurological Clinics 2007, 25(2),419-438).

Studies have shown that GABA_(B) agonists can be effective in treatingmuscular pain and/or spasms associated with peripheral musculoskeletalconditions. Baclofen has been shown to be effective in treating migraine(Hering-Hanit, Cephalalgia 1999, 19(6), 589-91; and Hering-Hanit andGadoth, Headache 2000, 40(1), 48-51) and specifically in tension-typeheadaches (Freitag, CNS Drugs 2003, 17(6), 373-81); and in low-back painand radiculopathy (Slonimski et al., Reg Anesth Pain Med 2004, 29(3),269-76; Dapas et al., Spine 1985, 10(4), 345-9; and Raphael et al., BMCMusculoskeletal Disorders 2002, 3(17).

The efficacy of crystalline(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid anhydrate and/or crystalline(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid hemihydrate for treating one or more types of musculoskeletal paincan be assessed in animal models of neuropathic pain and in clinicaltrials. For example, Kehl et al. disclose an animal model of musclehyperplasia that employs intramuscular injection of carrageenan asuseful for assessing the mechanisms and management of musculoskeletalpain (Kehl et al., Pain 2000, 85, 333-343).

Low back pain generally occurs in the lumbar region of the back in thelocation of lumbar vertebrae L1-L5. Pain in the lower back can be causedby a sprain, strain, or spasm to one of the muscles, ligaments, facetjoints, and/or sacroiliac joints in the back; spinal sprain orovercompression; or disc rupture or bulge. Low back pain may alsoreflect nerve or muscle irritation or bone lesions. Most low back painfollows injury or trauma to the back, but pain may also be caused bydegenerative conditions such as arthritis or disc disease, osteoporosis,or other bone diseases, viral infections, irritation to joints anddiscs, or congenital abnormalities in the spine. Obesity, smoking,weight gain during pregnancy, stress, poor physical condition, postureinappropriate for the activity being performed, and poor sleepingposition also may contribute to low back pain. Additionally, scar tissuecreated when the injured back heals itself does not have the strength orflexibility of normal tissue. Buildup of scar tissue from repeatedinjuries eventually weakens the back and can lead to more seriousinjury. Occasionally, low back pain may indicate a more serious medicalproblem. Pain accompanied by fever or loss of bowel or bladder control,pain when coughing, and progressive weakness in the legs may indicate apinched nerve or other serious condition. People with diabetes may havesevere back pain or pain radiating down the leg related to neuropathy.Low back pain can be caused by bulging disc(s) (e.g., protruding,herniated, or ruptured disc), sciatica, spinal degeneration, spinalstenosis, osteoporosis, osteoarthritis, compression fractures, skeletalirregularities, fibromyalgia, spondylolysis and/or spondylolisthesis.Less common spinal conditions that can cause low back pain includeankylosing spondylitis, bacterial infections, osteomyelitis, spinaltumors, Paget's disease, and Scheuermann's disease. Clinical resultssuggest that GABA_(B) agonists such as baclofen can be effective intreating low back pain (Dapas et al., Spine 1985, 10(4), 345-9; andRaphael et al., BMC Musculoskeletal Disorders 2002, 3(17). For example,doses of baclofen from about 20 mg/day to about 80/mg day have beenshown to be effective in treating acute low back pain (Dapas et al.,Spine 1985, 10(4), 345-9).

In certain embodiments, methods of treating low back pain provided bythe present disclosure comprises treating disorders, conditions, and/orsymptoms associated with low back pain such as muscle spasms. Symptomsof low back pain can depend on the cause. For example, symptoms of backsprain or back strain include muscle spasms, cramping, stiffness, andpain centered in the back and buttocks. Symptoms of nerve-root pressureinclude leg pain, also referred to as sciatica, and nerve-relatedmanifestations such as tingling, numbness, or weakness in one leg or inthe foot, lower leg, or both legs. Symptoms of arthritis of the spineinclude pain and stiffness that are worse in the back and hip.

Fibromyalgia is a condition characterized by aching and pain in muscles,tendons and joints all over the body, but especially along the spine.The body also is tender to touch in specific areas referred to as tenderor trigger points. Other symptoms of fibromyalgia include sleepdisturbance, depression, daytime tiredness, headaches, alternatingdiarrhea and constipation, numbness and tingling in the hands and feet,feelings of weakness, memory difficulties, and dizziness. Although theetiology of fibromyalgia is not known, stress, disordered sleeppatterns, abnormal production of pain-related chemicals in the nervoussystem, and/or low levels of growth hormone are believed to contributeto the onset of fibromyalgia.

Fibromyalgia usually occurs in people between 20 and 60 years of age andis estimated to affect 3.4% of women and 0.5% of men. The incidence ofjuvenile primary fibromyalgia in school age girls is estimated to beabout 1.2%.

Current treatment of fibromyalgia is based on symptoms, with the goalsof alleviating pain, restoring sleep, and improving general quality oflife. Several nonpharmacologic treatments include exercise, education,behavioral therapy and physical therapy. Pharmacologic treatmentsinclude tricyclic compounds, serotonin reuptake inhibitors, analgesics,muscle relaxants, and acetylcholine esterase inhibitors. There isevidence suggesting that GABA_(B) agonists such as baclofen may beuseful in improving fibromyalgia symptoms (Taylor-Gjevre and Gjevre,Lupus 2005, 14(6), 486-8).

The efficacy of crystalline(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid anhydrate and/or crystalline(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid hemihydrate for treating fibromyalgia may be assessed using animalmodels of fibromyalgia and in clinical results (see e.g., Dooley et al.,U.S. Patent Application Publication Nos. 2004/0180959 and 2004/0138305;Crofford et al., Arthritis & Rheumatism 2005, 52, 4, 1264-1273; Eaton, JRehabilitation Research and Development 2003, 40(4), 41S-54S; Guay, Am JGeriatr Pharmacother 2005, 3, 274-287; Freynhagen et al., Pain 2005,115, 254-263; Backonja et al., Clin Ther. 2003, 25, 81-104; Gidal etal., Am J Manag Care. 2006, 12, S269-S278; and Argoff, JAOA, 2002,Suppl. 3, 102(9), S21-S26). In particular, animal models of neuropathicpain or clinically relevant studies of different types of neuropathicpain have been found useful in assessing therapeutic activity fortreating fibromyalgia, such as are disclosed, for example, in Bennettand Xie, Pain 1988, 33, 87-107; Chaplan et al., J. Neurosci. Meth. 1994,53, 55-63; Fox et al., Pain 2003, 105, 355-362; Milligan et al., BrainRes. 2000, 861, 105-116; De Vry et al., Eur. J. Pharmacol. 2004, 491,137-148; and Polomano et al., Pain 2001, 94, 293-304.

Modes of Administration

Crystalline(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid anhydrate, or a pharmaceutical composition thereof, may beadvantageously used in human medicine. Additionally, crystalline(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid hemihydrate, or a pharmaceutical composition thereof, may beadvantageously used in human medicine. As disclosed herein, crystalline(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid anhydrate, or a pharmaceutical composition thereof, and/orcrystalline(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid hemihydrate, or a pharmaceutical composition thereof, are usefulfor the treatment of spasticity, gastroesophageal reflux disease,emesis, cough, substance addiction and abuse, neuropathic pain andmusculoskeletal pain.

When used to treat the above diseases, crystalline(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid anhydrate, or a pharmaceutical composition thereof, and/orcrystalline(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid hemihydrate, or a pharmaceutical composition thereof, may beadministered or applied singly, or in combination with other agents.Crystalline(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid anhydrate, or a pharmaceutical composition thereof, and/orcrystalline(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid hemihydrate, or a pharmaceutical composition thereof, may also beadministered or applied singly or in combination with otherpharmaceutically active agents, including other GABA analogs.

Methods of treatment include administering to a patient in need of suchtreatment a therapeutically effective amount of crystalline(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid anhydrate, or a pharmaceutical composition thereof, and/oradministering to a patient in need of such treatment a therapeuticallyeffective amount of crystalline(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid hemihydrate, or a pharmaceutical composition thereof. The patientmay be an animal, such as a mammal, for example, a human.

Crystalline(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid anhydrate, or a pharmaceutical composition thereof, and/orcrystalline(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid hemihydrate, or a pharmaceutical composition thereof, can beadministered orally. Crystalline(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid anhydrate, or a pharmaceutical composition thereof, and/orcrystalline(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid hemihydrate, or a pharmaceutical composition thereof, may also beadministered by any other convenient route, for example, by infusion orbolus injection, or by absorption through epithelial or mucocutaneouslinings (e.g., oral mucosa, rectal and intestinal mucosa, etc.).Administration can be systemic or local. Various delivery systems areknown, (e.g., encapsulation in liposomes, microparticles, microcapsules,capsules, etc.) that can be used to administer crystalline(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid anhydrate, or a pharmaceutical composition thereof, and/or that canbe used to administer crystalline(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid hemihydrate, or a pharmaceutical composition thereof. Methods ofadministration include, but are not limited to, intradermal,intramuscular, intraperitoneal, intravenous, subcutaneous, intranasal,epidural, oral, sublingual, intranasal, intracerebral, intravaginal,transdermal, rectally, by inhalation, or topically, particularly to theears, nose, eyes or skin.

In certain embodiments, crystalline(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid anhydrate, or a pharmaceutical composition thereof, and/orcrystalline(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid hemihydrate, or a pharmaceutical composition thereof, may bedelivered via sustained release systems, such as an oral sustainedrelease system.

Both crystalline(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid anhydrate, or a pharmaceutical composition thereof, and crystalline(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid hemihydrate, or a pharmaceutical composition thereof, exhibitenhanced bioavailability as (R)-baclofen compared to the bioavailabilityof (R)-baclofen when administered in an equivalent dosage form ofR-baclofen and/or racemate. The enhanced bioavailability of crystalline(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid anhydrate, or a pharmaceutical composition thereof, and crystalline(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid hemihydrate, or a pharmaceutical composition thereof, is believedto be due the efficient absorption of crystalline(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid anhydrate and crystalline(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid hemihydrate throughout the gastrointestinal tract, including thecolon, via passive and/or active transport mechanisms.

Both crystalline(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid anhydrate, or a pharmaceutical composition thereof, and crystalline(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid hemihydrate, or a pharmaceutical composition thereof, provide(R)-baclofen upon in vivo administration to a patient. Crystalline(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid anhydrate and/or crystalline(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid hemihydrate, or a metabolite thereof, may be absorbed into thesystemic circulation from the gastrointestinal tract either by passivediffusion, active transport or by both passive and active processes.

Following administration to a patient, crystalline(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid anhydrate, or a pharmaceutical composition thereof, and crystalline(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid hemihydrate, or a pharmaceutical composition thereof, provide(R)-baclofen in the systemic circulation of a patient. Crystalline(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid anhydrate and/or crystalline(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid hemihydrate may be absorbed from the gastrointestinal tract andenter the systemic circulation where the promoiety is cleaved to release(R)-baclofen.

When administered to a patient, for example, by a patient swallowing adosage form comprising the compounds disclosed herein, crystalline(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid anhydrate and/or crystalline(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid hemihydrate provide a sustained therapeutically effectiveconcentration of (R)-baclofen in the blood of a patient during acontinuous period of time. In certain embodiments, crystalline(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid anhydrate and/or crystalline(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid hemihydrate may provide a concentration of (R)-baclofen in theblood of a patient that is greater than a minimum therapeuticallyeffective concentration and less than a minimum adverse concentration of(R)-baclofen in the blood of the patient. In certain embodiments,crystalline(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid anhydrate and/or crystalline(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid hemihydrate provide a therapeutically effective concentration of(R)-baclofen in the blood of a patient for a continuous period of timewithout exceeding the minimum adverse concentration of (R)-baclofen. Incertain embodiments, the concentration of (R)-baclofen in the blood of apatient does not exceed a minimum adverse concentration at any timeafter crystalline(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid anhydrate and/or crystalline(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid hemihydrate is administered to a patient.

The promoiety of crystalline(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid anhydrate and/or crystalline(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid hemihydrate may be cleaved either chemically and/or enzymatically.One or more enzymes present in the stomach, intestinal lumen, intestinaltissue, blood, liver, brain or any other tissue of a mammal may cleavethe promoiety of crystalline(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid anhydrate and/or crystalline(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid hemihydrate. The promoiety of crystalline(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid anhydrate and/or crystalline(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid hemihydrate may be cleaved prior to absorption by thegastrointestinal tract (e.g., within the stomach or intestinal lumen)and/or after absorption by the gastrointestinal tract (e.g., inintestinal tissue, blood, liver or other suitable tissue of a mammal).When the promoiety of crystalline(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid anhydrate and/or crystalline(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid hemihydrate is cleaved prior to absorption by the gastrointestinaltract, baclofen may be absorbed into the systemic circulationconventionally (e.g., mediated, in part, via the large neutral aminoacid transporter located in the small intestine). When the promoiety ofcrystalline(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid anhydrate and/or crystalline(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid hemihydrate is cleaved after absorption by the gastrointestinaltract, these baclofen prodrugs may be absorbed into the systemiccirculation either by passive diffusion, active transport, or by bothpassive and active processes.

When the promoiety of crystalline(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid anhydrate and/or crystalline(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid hemihydrate is cleaved after absorption by the gastrointestinaltract, these baclofen prodrugs may be absorbed into the systemiccirculation from the large intestine. When absorbed by the largeintestine, crystalline(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid anhydrate, or a pharmaceutical composition thereof, and/orcrystalline(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid hemihydrate, or a pharmaceutical composition thereof, can beadvantageously administered as a sustained release system. In certainembodiments, crystalline(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid anhydrate, or a pharmaceutical composition thereof, and/orcrystalline(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid hemihydrate, or a pharmaceutical composition thereof, can bedelivered by oral sustained release administration. When administeredusing a sustained release formulation, crystalline(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid anhydrate, or a pharmaceutical composition thereof, and/orcrystalline(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid hemihydrate, or a pharmaceutical composition thereof, can beadministered once per day, twice per day, or in some embodiments morethan twice per day.

Crystalline(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid anhydrate and/or crystalline(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid hemihydrate can provide a therapeutically effective concentrationof (R)-baclofen in the blood of a patient for a continuous period oftime while reducing or eliminating adverse drug effects associated withhigh blood concentrations of (R)-baclofen, e.g., at concentrations abovethe minimum adverse concentration, that are observed following dosing of(R)-baclofen itself. The high bioavailability of (R)-baclofen that isachievable by administering crystalline(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid anhydrate and/or crystalline(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid hemihydrate may facilitate the use of lower mass equivalents of(R)-baclofen in a dose to achieve a sustained therapeutically effectiveconcentration of (R)-baclofen in the blood of a patient, as compared tothe amount of (R)-baclofen in a dosage form comprising (R)-baclofenitself.

In certain embodiments, administration of a sustained release dosageform comprising crystalline(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid anhydrate and/or crystalline(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid hemihydrate can provide a therapeutically effective concentrationof (R)-4-amino-3-(4-chlorophenyl)butanoic acid in the blood plasma of apatient for a time period of at least about 4 hours after administrationof the dosage form, in certain embodiments for a time period of at leastabout 8 hours, in certain embodiments for a time period of at leastabout 12 hours, in certain embodiments for a time period of at leastabout 16 hours, in certain embodiments for a time period of at leastabout 20 hours, and in certain embodiments, for a time period of atleast about 24 hours.

In certain embodiments, the concentration of (R)-baclofen in the bloodof a patient will not exceed a minimum adverse concentration at any timeafter crystalline(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid anhydrate and/or crystalline(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid hemihydrate is administered to the patient. For example, theconcentration of (R)-baclofen in the blood of a patient will not reach aconcentration that causes adverse events in the patient. Atherapeutically effective concentration of (R)-baclofen in the blood ofa patient may range from about 50 ng/mL to about 1,000 ng/mL, and incertain embodiments, from about 100 ng/mL to about 500 ng/mL. Thepharmacokinetic profile of the blood (R)-baclofen concentrationachievable upon administration of crystalline(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid anhydrate and/or crystalline(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid hemihydrate to a patient can be characterized by a lowerC_(max)/C₁₂ ratio, and a lower C_(max)/dose, as compared to formulationscomprising (R)-baclofen itself that provide a similar (R)-baclofen bloodAUC_(inf).

Pharmaceutical Compositions

Pharmaceutical compositions provided by the present disclosure containcrystalline(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid anhydrate and/or crystalline(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid hemihydrate together with a suitable amount of a pharmaceuticallyacceptable vehicle so as to provide a form for proper oraladministration to a patient. In certain embodiments, pharmaceuticalcompositions provided by the present disclosure contain atherapeutically effective amount of crystalline(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid anhydrate and/or crystalline(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid hemihydrate together with a suitable amount of a pharmaceuticallyacceptable vehicle so as to provide a form for proper oraladministration to a patient. Suitable pharmaceutical vehicles includeexcipients such as starch, glucose, lactose, sucrose, gelatin, malt,rice, flour, chalk, silica gel, sodium stearate, glycerol monostearate,talc, sodium chloride, dried skim milk, glycerol, propylene, glycol,water, ethanol, etc. Pharmaceutical compositions provided by the presentdisclosure may also contain minor amounts of wetting or emulsifyingagents or pH buffering agents. In addition, auxiliary, stabilizing,thickening, lubricating and coloring agents may be used.

Pharmaceutical compositions comprising crystalline(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid anhydrate and/or crystalline(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid hemihydrate may be manufactured by means of mixing, dissolving,granulating, dragee-making, levigating, emulsifying, encapsulating,entrapping, lyophilizing, or other process known to those skilled in theart of pharmaceutical formulation. Pharmaceutical compositions may beformulated using one or more pharmaceutically acceptable vehicles thatfacilitate processing crystalline(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid anhydrate and/or crystalline(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid hemihydrate into oral dosage formulations, such as sustainedrelease oral dosage formulations.

Pharmaceutical compositions provided by the present disclosure can takethe form of solutions, aqueous or oily suspensions, emulsion, tablets,pills, pellets, capsules, capsules containing liquids, granules,powders, sustained-release formulations, suppositories, emulsions,syrups, elixirs or any other form suitable for oral administration.Orally administered pharmaceutical compositions may contain one or moreoptional agents, for example, sweetening agents such as fructose,aspartame or saccharin, flavoring agents such as peppermint, oil ofwintergreen or cherry coloring agents and preserving agents, to providea pharmaceutically palatable preparation. Moreover, where in tablet orpill form, the pharmaceutical compositions may be coated to delaydisintegration and absorption in the gastrointestinal tract, therebyproviding a sustained action over an extended period of time.Selectively permeable membranes surrounding an osmotically activedriving compound are also suitable for orally administering thecompounds and compositions disclosed herein. In these later platforms,fluid from the environment surrounding the capsule is imbibed by thedriving compound, which swells to displace the agent or agentcomposition through an aperture. These delivery platforms can provide anessentially zero order delivery profile as opposed to the spikedprofiles of immediate release formulations. A time delay material suchas glycerol monostearate or glycerol stearate may also be used. Oralpharmaceutical compositions can include pharmaceutically acceptablevehicles such as mannitol, lactose, starch, magnesium stearate, sodiumsaccharine, cellulose, magnesium carbonate, and the like.

For oral liquid preparations such as, for example, suspensions, elixirsand solutions, suitable vehicles include water, saline, alkyleneglycols(e.g., propylene glycol), polyalkylene glycols (e.g., polyethyleneglycol) oils, alcohols, slightly acidic buffers between pH 4 and pH 6(e.g., acetate, citrate, ascorbate at between about 5 mM to about 50mM), etc. Additionally, flavoring agents, preservatives, coloringagents, bile salts, acylcarnitines and the like may be added.

Crystalline(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid anhydrate and/or crystalline(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid hemihydrate may be formulated in rectal or vaginal compositionssuch as suppositories or retention enemas, e.g., containing conventionalsuppository bases such as cocoa butter or other glycerides.

In certain embodiments, crystalline(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid anhydrate and/or crystalline(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid hemihydrate can be formulated as a single active agent. In certainembodiments, crystalline(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid anhydrate and crystalline(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid hemihydrate can be formulated as a mixture. In certain embodiments,crystalline(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid anhydrate and/or crystalline(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid hemihydrate can be formulates as a mixture with one or more otherbaclofen prodrugs or salts thereof such as, for example,(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid.

Kits

Crystalline(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid anhydrate, or a pharmaceutical composition thereof, and/orcrystalline(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid hemihydrate, or a pharmaceutical composition thereof, may beincluded in a kit that may be used to administer either compound, orboth, to a patient for treating a disease. A kit can include apharmaceutical composition comprising crystalline(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid anhydrate and/or crystalline(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid hemihydrate suitable for administration to a patient andinstructions for administering the pharmaceutical composition to apatient. A kit can include one or more containers for containing one ormore pharmaceutical compositions and may include divided containers suchas a divided bottle or a divided foil packet. A container can be anyappropriate shape or form made of a pharmaceutically acceptablematerial. A particular container can depend on the dosage form and thenumber of dosage forms provided. Instructions provided with a kit caninclude directions for administration and may include a memory aid.Instructions supplied with a kit may be printed and/or supplied, forexample, as an electronic-readable medium, a video cassette, anaudiotape, a flash memory device, or may be published on an internet website or distributed to a patient as an electronic mail. A memory aid maybe a written memory aid, which contains information and/or instructionsfor the physician, pharmacist, and/or patient to facilitate compliancewith a dosing regimen. A memory aid may also be mechanical orelectronic. When a therapeutic regimen includes administration ofcrystalline(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid anhydrate and/or crystalline(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid hemihydrate and at least one other therapeutic agent, a kit caninclude the at least one other therapeutic agent in the same or separatecontainer as the crystalline(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid anhydrate and/or crystalline(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid hemihydrate.

In certain embodiments, a kit comprises a pharmaceutical compositioncomprising crystalline(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid anhydrate and instructions for administering the pharmaceuticalcomposition to a patient in need thereof for treating a disease chosenfrom spasticity, gastroesophageal reflux disease, emesis, cough,substance addiction and abuse, neuropathic pain and musculoskeletalpain. In certain embodiments, a kit comprises a pharmaceuticalcomposition comprising crystalline(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid hemihydrate and instructions for administering the pharmaceuticalcomposition to a patient in need thereof for treating a disease chosenfrom spasticity, gastroesophageal reflux disease, emesis, cough,substance addiction and abuse, neuropathic pain and musculoskeletalpain.

In certain embodiments, a kit comprises a pharmaceutical compositioncomprising crystalline(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid anhydrate and instructions for administering the pharmaceuticalcomposition to a patient in need thereof for treating spasticity. Incertain embodiments, a kit comprises a pharmaceutical compositioncomprising crystalline(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid hemihydrate and instructions for administering the pharmaceuticalcomposition to a patient in need thereof for treating spasticity.

In certain embodiments, a kit comprises a pharmaceutical compositioncomprising crystalline(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid anhydrate and instructions for administering the pharmaceuticalcomposition to a patient in need thereof for treating gastroesophagealreflux disease. In certain embodiments, a kit comprises a pharmaceuticalcomposition comprising crystalline(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid hemihydrate and instructions for administering the pharmaceuticalcomposition to a patient in need thereof for treating gastroesophagealreflux disease.

In certain embodiments, a kit comprises a pharmaceutical compositioncomprising crystalline(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid anhydrate and instructions for administering the pharmaceuticalcomposition to a patient in need thereof for treating substanceaddiction or abuse. In certain embodiments, a kit comprises apharmaceutical composition comprising crystalline(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid hemihydrate and instructions for administering the pharmaceuticalcomposition to a patient in need thereof for treating substanceaddiction or abuse.

In certain embodiments, a kit comprises a pharmaceutical compositioncomprising crystalline(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid anhydrate and instructions for administering the pharmaceuticalcomposition to a patient in need thereof for treating cough. In certainembodiments, a kit comprises a pharmaceutical composition comprisingcrystalline(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid hemihydrate and instructions for administering the pharmaceuticalcomposition to a patient in need thereof for treating cough.

In certain embodiments, a kit comprises a pharmaceutical compositioncomprising crystalline(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid anhydrate and instructions for administering the pharmaceuticalcomposition to a patient in need thereof for treating emesis. In certainembodiments, a kit comprises a pharmaceutical composition comprisingcrystalline(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid hemihydrate and instructions for administering the pharmaceuticalcomposition to a patient in need thereof for treating emesis.

In certain embodiments, a kit comprises a pharmaceutical compositioncomprising crystalline(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid anhydrate and instructions for administering the pharmaceuticalcomposition to a patient in need thereof for treating neuropathic pain.In certain embodiments, a kit comprises a pharmaceutical compositioncomprising crystalline(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid hemihydrate and instructions for administering the pharmaceuticalcomposition to a patient in need thereof for treating neuropathic pain.

In certain embodiments, a kit comprises a pharmaceutical compositioncomprising crystalline(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid anhydrate and instructions for administering the pharmaceuticalcomposition to a patient in need thereof for treating musculoskeletalpain. In certain embodiments, a kit comprises a pharmaceuticalcomposition comprising crystalline(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid hemihydrate and instructions for administering the pharmaceuticalcomposition to a patient in need thereof for treating musculoskeletalpain.

Dose

Crystalline(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid anhydrate, or a pharmaceutical composition thereof, and/orcrystalline(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid hemihydrate, or a pharmaceutical composition thereof, can generallybe used in an amount that is effective to achieve the intended purpose,such as to treat a disease or disorder selected from spasticity,gastroesophageal reflux disease, emesis, cough, substance addiction andabuse, neuropathic pain and/or musculoskeletal pain. Crystalline(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid anhydrate, or a pharmaceutical composition thereof, can beadministered in a therapeutically effective amount. Crystalline(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid hemihydrate, or a pharmaceutical composition thereof, can beadministered in a therapeutically effective amount.

The amount of crystalline(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid anhydrate, or a pharmaceutical composition thereof, and/or theamount of crystalline(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid hemihydrate, or a pharmaceutical composition thereof, that will beeffective in the treatment of a particular disease or disorder willdepend on the nature of the disorder or condition, and can be determinedby standard clinical techniques known in the art as previouslydescribed. In addition, in vitro or in vivo assays may optionally beemployed to help identify optimal dosage ranges. The amount ofcrystalline(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid anhydrate, or a pharmaceutical composition thereof, and/or theamount of crystalline(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid hemihydrate, or a pharmaceutical composition thereof, administeredwill depend on, among other factors, the subject being treated, theweight of the subject, the severity of the affliction, the manner ofadministration and the judgment of the prescribing physician.

A dose of crystalline(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid anhydrate and/or a dose of crystalline(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid hemihydrate can be adjusted to provide an equivalent molar quantityor mass equivalent dose of (R)-baclofen. A dose can comprise multipledosage forms. Therapeutically effective doses of (R)-baclofen aregenerally from about 0.03 mg to about 1 mg per kilogram body weight perday. In certain embodiments, a daily dose can comprise a mass equivalentof (R)-baclofen ranging from about 1 mg to about 100 mg, in certainembodiments, from about 5 mg to about 80 mg, in certain embodiments,from about 5 mg to about 60 mg, and in certain embodiments, from about10 mg to about 40 mg. In certain embodiments, a dose of crystalline(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid anhydrate and/or a dose of crystalline(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid hemihydrate is less than a dose that causes moderate sedation andimpairment of motor activity in a patient. The dose of crystalline(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid anhydrate and/or the dose of crystalline(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid hemihydrate, and appropriate dosing intervals, can be selected tomaintain a sustained therapeutically effective concentration of(R)-baclofen in the blood of a patient, and in certain embodiments,without exceeding a minimum adverse concentration.

A dose may be delivered in a pharmaceutical composition by a singleadministration or by multiple applications of one or more dosage forms.In certain embodiments, crystalline(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid anhydrate, or a pharmaceutical composition thereof, and/orcrystalline(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid hemihydrate, or a pharmaceutical composition thereof, can bedelivered by oral sustained release administration. A sustained releaseformulation comprising crystalline(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid anhydrate, or a pharmaceutical composition thereof, and/or asustained release formulation comprising crystalline(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid hemihydrate, or a pharmaceutical composition thereof, can beadministered once per day, twice per day and, in certain embodiments, atintervals greater than twice per day. Dosing may be repeatedintermittently, may be provided alone or in combination with otherdrugs, and may continue as long as required for effective treatment ofthe disease or disorder. Dosing includes administering a dosage form toa mammal, such as a human, in a fed or fasted state.

Appropriate dosage ranges for treating a particular disease may bereadily determined by methods known to the skilled artisan.

In certain embodiments, a dose or multiple doses of crystalline(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid anhydrate, or a pharmaceutical composition thereof, and/or a doseor multiple doses of crystalline(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid hemihydrate, or a pharmaceutical composition thereof, can providebetween about 10 mg/day and about 2,000 mg/day of (R)-baclofen, incertain embodiments between about 50 mg/day and about 1,000 mg/day of(R)-baclofen, and in certain embodiments, between about 100 mg/day andabout 600 mg/day of (R)-baclofen.

In certain embodiments, a dose or multiple doses of crystalline(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid anhydrate, or a pharmaceutical composition thereof, and/or a doseor multiple doses of crystalline(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid hemihydrate, or a pharmaceutical composition thereof, isadministered to a patient at a dose of crystalline(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid anhydrate and/or crystalline(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid hemihydrate ranging from about 5 mg to about 140 mg, and in certainembodiments, from about 10 mg to about 120 mg. In certain embodiments,the dose of crystalline(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid anhydrate and/or crystalline(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid hemihydrate administered is less than a dose of crystalline(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid anhydrate and/or crystalline(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid hemihydrate that causes moderate sedation and impairment of motoractivity in a patient.

A dosage regimen employing oral administration of a dose or multipledoses of crystalline(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid anhydrate, or a pharmaceutical composition thereof, and/or a doseor multiple doses of crystalline(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid hemihydrate, or a pharmaceutical composition thereof, may bedeveloped to maintain a concentration of (R)-baclofen in the blood of apatient that is greater than a minimum therapeutically effectiveconcentration and less than a minimum adverse concentration for aprolonged period of time. In certain embodiments, a minimumtherapeutically effective concentration of (R)-baclofen may range fromabout 1 ng/mL to about 200 ng/mL, and in certain embodiments, can rangefrom about 10 ng/mL to about 100 ng/mL. In certain embodiments, aminimum adverse concentration can range from about 200 ng/mL to about2,000 ng/mL, and in certain embodiments, can range from about 500 ng/mLto about 1,000 ng/mL. A minimum therapeutic concentration and a minimumadverse concentration will depend on a number of factors such as thedisease being treated, the severity of the disease, the intendedclinical outcome, the condition of the patient being treated, and soforth. An appropriate interval of dosing may depend, for example, on theamount of crystalline(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid anhydrate and/or crystalline(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid hemihydrate in the dosage form, the composition of the dosage form,the release characteristics of crystalline(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid anhydrate and/or crystalline(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid hemihydrate from the dosage form, the disease being treated, thecondition of the patient, the potential adverse effects, and thejudgment of the prescribing physician. Dosage regimens may includerepeated administration of the same dosage form at each interval ordifferent dosage forms at different intervals. For example, atwice-daily dosage regimen can include the administration of a firstdosage form in the morning, and a second dosage form in the evening.

Crystalline(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid anhydrate, or a pharmaceutical composition thereof, and/orcrystalline(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid hemihydrate, or a pharmaceutical composition thereof, can beassayed in vitro and in vivo, for the desired therapeutic orprophylactic activity, prior to use in humans. A therapeuticallyeffective dose of crystalline(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid anhydrate, or a pharmaceutical composition thereof, and/or atherapeutically effective dose of crystalline(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid hemihydrate, or a pharmaceutical composition thereof, can providetherapeutic benefit without causing substantial toxicity and/or adverseside effects. The toxicity and adverse side effects of crystalline(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid anhydrate, or a pharmaceutical composition thereof, and/or ofcrystalline(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid hemihydrate, or a pharmaceutical composition thereof, may bedetermined using standard pharmaceutical procedures and may be readilyascertained by the skilled artisan. The dose ratio between toxic andadverse side effects and therapeutic effect is the therapeutic index. Adose of crystalline(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid anhydrate, or a pharmaceutical composition thereof, and/or a doseof crystalline(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid hemihydrate, or a pharmaceutical composition thereof, can provide acirculating concentration of (R)-baclofen that is within atherapeutically effective concentration with little or no toxicity oradverse side effects.

Combination Therapy

Dosage forms comprising crystalline(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid anhydrate, or a pharmaceutical composition thereof, and/or dosageforms comprising crystalline(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid hemihydrate, or a pharmaceutical composition thereof, may furthercomprise one or more pharmaceutically active compounds in addition tocrystalline(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid anhydrate and/or crystalline(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid hemihydrate. Such compounds may be provided to treat the samedisease or a different disease than the disease being treated withcrystalline(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid anhydrate and/or crystalline(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid hemihydrate.

In certain embodiments, crystalline(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid anhydrate, or a pharmaceutical composition thereof, can be used incombination therapy with at least one other therapeutic agent.Crystalline(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid anhydrate, or a pharmaceutical composition thereof, and the atleast one other therapeutic agent can act additively or synergistically.In certain embodiments, crystalline(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid hemihydrate, or a pharmaceutical composition thereof, can be usedin combination therapy with at least one other therapeutic agent.Crystalline(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid hemihydrate, or a pharmaceutical composition thereof, and the atleast one other therapeutic agent can act additively or synergistically.

In certain embodiments, a pharmaceutical composition comprisingcrystalline(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid anhydrate can be administered concurrently with the administrationof another therapeutic agent, which can be part of the samepharmaceutical composition as crystalline(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid anhydrate, or the other therapeutic agent can be in a differentpharmaceutical composition. In certain embodiments, a pharmaceuticalcomposition comprising crystalline(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid hemihydrate can be administered concurrently with theadministration of another therapeutic agent, which can be part of thesame pharmaceutical composition as crystalline(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid hemihydrate, or the other therapeutic agent can be in a differentpharmaceutical composition. In certain embodiments, a pharmaceuticalcomposition comprising crystalline(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid anhydrate, and/or a pharmaceutical composition comprisingcrystalline(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid hemihydrate, can be administered prior to or subsequent toadministration of another therapeutic agent.

In certain embodiments, crystalline(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid anhydrate and/or crystalline(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid hemihydrate may be administered in combination with an amorphousform of(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid; other crystalline form(s) of(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid; baclofen; (R)-baclofen; or a combination of any of the foregoing.

In certain embodiments, crystalline(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid anhydrate and/or crystalline(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid hemihydrate may be used in combination with at least one othertherapeutic agent. In certain embodiments, crystalline(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid anhydrate and/or crystalline(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid hemihydrate may be administered to a patient together with anothercompound for treating movement disorders such as spasticity, digestivedisorders such as gastro-esophageal reflux disease and emesis, oraddictive or abuse disorders such as nicotine addiction or abuse,alcohol addiction or abuse, narcotic addiction or abuse, cough,neuropathic pain, or musculoskeletal pain. In certain embodiments, theat least one other therapeutic agent may be a different (R)-baclofenprodrug. Crystalline(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid anhydrate and/or crystalline(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid hemihydrate and the at least one other therapeutic agent may actadditively or, in certain embodiments, synergistically.

Accordingly, methods provided by the present disclosure can furtherinclude, in addition to administering crystalline(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid anhydrate and/or crystalline(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid hemihydrate, administering one or more therapeutic agents effectivefor treating the same disease as, or a different disease than, thedisease being treated by crystalline(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid anhydrate and/or crystalline(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid hemihydrate. Methods provided by the present disclosure includeadministration of crystalline(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid anhydrate and/or crystalline(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid hemihydrate and one or more other therapeutic agents, provided,however, that the combined administration does not inhibit thetherapeutic efficacy of crystalline(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid anhydrate and/or crystalline(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid hemihydrate and/or does not produce adverse combination effects.

In certain embodiments, crystalline(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid anhydrate and/or crystalline(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid hemihydrate may be administered concurrently with theadministration of another therapeutic agent, which may be part of thesame dosage form as, or in a different dosage form than that comprisingcrystalline(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid anhydrate and/or crystalline(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid hemihydrate. Crystalline(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid anhydrate and/or crystalline(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid hemihydrate may be administered prior to, or subsequent to,administration of another therapeutic agent. In certain embodiments ofcombination therapy, the combination therapy may comprise alternatingbetween: administering crystalline(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid anhydrate and/or crystalline(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid hemihydrate; and administering a composition comprising anothertherapeutic agent, e.g., to minimize adverse drug effects associatedwith a particular drug. When crystalline(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid anhydrate and/or crystalline(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid hemihydrate is administered concurrently with another therapeuticagent that may potentially produce an adverse drug effect including, butnot limited to, toxicity, the other therapeutic agent may advantageouslybe administered at a dose that falls below the threshold at which theadverse drug reaction is elicited.

In certain embodiments, crystalline(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid anhydrate and/or crystalline(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid hemihydrate may be administered with one or more substances toenhance, modulate and/or control release, bioavailability, therapeuticefficacy, therapeutic potency, stability, and the like of crystalline(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid anhydrate and/or crystalline(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid hemihydrate. For example, to enhance the therapeutic efficacy ofcrystalline(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid anhydrate and/or crystalline(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid hemihydrate or the metabolite of such compounds, (R)-baclofen,crystalline(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid anhydrate and/or crystalline(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid hemihydrate may be co-administered with, or a dosage formcomprising crystalline(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid anhydrate and/or crystalline(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid hemihydrate may comprise, one or more active agents that act toincrease the absorption or diffusion of crystalline(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid anhydrate and/or crystalline(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid hemihydrate or (R)-baclofen from the gastrointestinal tract to thesystemic circulation, or to inhibit degradation of crystalline(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid anhydrate and/or crystalline(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid hemihydrate or (R)-baclofen in the blood of a patient. In certainembodiments, crystalline(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid anhydrate and/or crystalline(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid hemihydrate may be co-administered with an active agent havingpharmacological affects that enhance the therapeutic efficacy ofcrystalline(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid anhydrate and/or crystalline(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid hemihydrate.

Additionally, crystalline(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid anhydrate and/or crystalline(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid hemihydrate may be used in combination with other drugs that arethemselves known to cause spasticity, gastroesophageal reflux disease,emesis, cough, substance addiction and abuse, neuropathic pain and/ormusculoskeletal pain as an adverse effect, thereby preventing orreducing the occurrence of such adverse effects.

In certain embodiments, crystalline(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid anhydrate and/or crystalline(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid hemihydrate may be administered to a patient for treating amovement disorder such as spasticity in combination with a therapy oranother therapeutic agent known or believed to be effective in treatinga movement disorder such as spasticity. Examples of drugs for treatingmovement disorders such as spasticity and which may be administered inconjunction with crystalline(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid anhydrate and/or crystalline(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid hemihydrate include levodopa; mild sedatives such asbenzodiazepines including alprazolam, chlordiazepoxide, clonazepam,clorazepate, diazepam, lorazepam, and oxazepam; muscle relaxants such asbaclofen; anticholinergic drugs such as trihexyphenidyl anddiphenhydramine; antipsychotics such as chlorpromazine, fluphenazine,haloperidol, loxapine, mesoridazine, molindone, perphenazine, pimozide,thioridazine, thiothixene, trifluoperazine, aripiprazole, clozapine,olanzapine, quetiapine, risperidone, and ziprasidone; andantidepressants such as amitriptyline.

In certain embodiments, crystalline(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid anhydrate and/or crystalline(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid hemihydrate may be administered to a patient for treating agastrointestinal disorder such as gastro-esophageal reflux disease incombination with a therapy or another therapeutic agent known orbelieved to be effective in treating a gastrointestinal disorder such asgastro-esophageal reflux disease. Examples of drugs for treatinggastrointestinal disorders such as gastro-esophageal reflux disease andwhich may be administered in conjunction with crystalline(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid anhydrate and/or crystalline(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid hemihydrate include H₂-receptor inhibitors such as cimetidine,famotidine, nizatidine, and ranitidine; proton pump inhibitors such asomeprazole, lansoprazole, pantoprazole, rabeprazole, and exomeprazole;and prokinetics such as cisparide, bethanechol, and metoclopramide.

In certain embodiments, crystalline(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid anhydrate and/or crystalline(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid hemihydrate may be administered to a patient for treating emesis incombination with a therapy or another therapeutic agent known orbelieved to be effective in treating emesis. Examples of drugs fortreating emesis (nausea and vomiting) and which may be administered inconjunction with crystalline(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid anhydrate and/or crystalline(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid hemihydrate include benzamines such as metoclopramide;phenothiazines such as prochlorperazine, perphenazine, chlorpromazine,promethazine, and thiethylperazine; butyrophenones such as droperidoland haloperidol; dopamine 2 antagonists such as metoclorpamide; 5-HT₃antagonists such as ondansetron, granisetron, dolasetron, palonosetron;NK-1 receptor antagonists such as aprepitant, corticosteroids such asdexamethazone; antihistamines such as diphenhydramine and hydroxyzine;cannabinoids such as dronabinol; and benzodiazepines such as lorazepam,midazolam, alprazolam, and olanzapine.

In certain embodiments, crystalline(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid anhydrate and/or crystalline(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid hemihydrate may be administered to a patient for treating alcoholaddiction or abuse in combination with a therapy or another therapeuticagent known or believed to be effective in treating alcohol addiction orabuse. Examples of drugs for treating alcohol addiction or abuse andwhich may be administered in conjunction with crystalline(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid anhydrate and/or crystalline(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid hemihydrate include disulfuram, naltrexone, clonidine, methadone,1-alpha-acetylmethadol, buprenorphine, and bupropion.

In certain embodiments, crystalline(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid anhydrate and/or crystalline(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid hemihydrate may be administered to a patient for treating narcoticaddiction or abuse in combination with a therapy or another therapeuticagent known or believed to be effective in treating narcotic addictionor abuse. Examples of drugs for treating narcotic addiction or abuse andwhich may be administered in conjunction with crystalline(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid anhydrate and/or crystalline(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid hemihydrate include buprenorphine, tramadol, methadone, andnaltrexone.

In certain embodiments, crystalline(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid anhydrate and/or crystalline(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid hemihydrate may be administered to a patient for treating nicotineaddiction or abuse in combination with a therapy or another therapeuticagent known or believed to be effective in treating nicotine addictionor abuse. Examples of drugs for treating nicotine addiction or abuse andwhich may be administered in conjunction with crystalline(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid anhydrate and/or crystalline(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid hemihydrate include bupropion, clonidine, and nicotine.

In certain embodiments, crystalline(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid anhydrate and/or crystalline(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid hemihydrate may be administered to a patient for treating cough incombination with a therapy or another therapeutic agent known orbelieved to be effective in treating cough. Examples of drugs fortreating cough and which may be administered in conjunction withcrystalline(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid anhydrate and/or crystalline(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid hemihydrate include dextromethorphan, guaifenesin, hydrocodone,benzonatate, diphenhydramine, pseudoephedrine, acetaminophen, andcarbinoxamine.

In certain embodiments, crystalline(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid anhydrate and/or crystalline(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid hemihydrate may be administered to a patient for treatingneuropathic pain in combination with a therapy or another therapeuticagent known or believed to be effective in treating neuropathic pain.Examples of drugs useful for treating pain and which may be administeredin conjunction with crystalline(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid anhydrate and/or crystalline(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid hemihydrate include opioid analgesics such as morphine, codeine,fentanyl, meperidine, methadone, propoxyphene, levorphanol,hydromorphone, oxycodone, oxymorphone, tramadol and pentazocine;nonopioid analgesics such as aspirin, ibuprofen, ketoprofen, naproxen,and acetaminophen; non-steroidal anti-inflammatory drugs such asaspirin, choline magnesium trisalicylate, diflunisal, salsalate,celecoxib, rofecoxib, valdecoxib, diclofenac, etodolac, fenoprofen,flubiprofen, ibuprofen, indomethacin, ketoprofen, ketorolac,meclofanamate, mefenamic acid, meloxicam, nabumetone, naproxen,oxaprozin, piroxicam, sulindac, and tometin; antiepileptics such asgabapentin, pregabalin, carbamazepine, phenyloin, lamotrigine, andtopiramate; antidepressants such as duloxetine, amitriptyline,venlafaxine, nortryptyline, imipramine, and desipramine; localanesthetics such as lidocaine, and mexiletine; NMDA receptor antagonistssuch as dextropethorphan, memantine, and ketamine; N-typecalcium-channel blockers such as ziconotide; vanilloid receptor-1modulators such as capsaicin; cannabinoid receptor modulators such assativex; neurokinin receptor antagonists such as lanepitant; otheranalgesics such as neurotropin; and other drugs such as desipramine,clonazepam, divalproex, oxcarbazepine, divalproex, butorphanol,valdecoxib, vicoprofen, pentazocine, propoxyhene, fenoprofen, piroxicam,indometnacin, hydroxyzine, buprenorphine, benzocaine, clonidine,flurbiprofen, meperidine, lacosamide, desvenlafaxine, and bicifadine.

In certain embodiments, a drug useful for treating neuropathic pain andwhich may be administered in conjunction with crystalline(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid anhydrate and/or crystalline(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid hemihydrate is chosen from propoxyphene, meperidine, hydromorphone,hydrocodone, morphine, codeine, 2-piperidinol-1-alkanol, eliprodil,ifenprodil, rofecoxib, celecoxib, salicylic acid, diclofenac, piroxicamindomethacin, ibuprofen, naproxen, gabapentin, carbemazepine,pregabalin, topiramate, valproic acid, sumatriptan, elitriptan,rizatriptan, zolmitriptan, naratriptan, flexeril, carisoprodol,robaxisal, norgesic, dantrium, diazepam, chlordiazepoxide, alprazolam,lorazepam, acetaminophen, nitrous oxide, halothane, lidocaine,etidocaine, ropivacaine, chloroprocaine, sarapin, bupivacaine, capsicin,desipramine, amitriptyline, doxepin, perphenazine, protriptyline,tranylcypromine, baclofen, clonidine, mexelitine, diphenhydramine,hydroxyzine, caffeine, prednisone, methyl-prednisone, decadron,sertraline, paroxetine, fluoxetine, tramadol, levodopa,dextromethorphan, substance P antagonists, and botulinum toxin.

In certain embodiments, a drug useful for treating neuropathic pain andwhich may be administered in conjunction with crystalline(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid anhydrate and/or crystalline(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid hemihydrate is chosen from a nicotine receptor partial agonist andan analgesic agent as disclosed by Coe et al., U.S. Patent ApplicationPublication No. 2003/0133951; a 1-aryl-3-azabicyclo[3.1.0]hexane asdisclosed by Lippa et al., U.S. Patent Application Publication No.2007/00892939; and a nitro(cyano)vinylpiperazine compound as disclosedby Sun and Tafesse, U.S. Patent Application Publication No.2007/0032500.

Non-pharmacological therapies for treating neuropathic pain and whichmay be administered in conjunction with crystalline(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid anhydrate and/or crystalline(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid hemihydrate include transcutaneous electrical nerve stimulation,percutaneous electrical nerve stimulation, and acupuncture.

In certain embodiments, crystalline(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid anhydrate and/or crystalline(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid hemihydrate may be administered to a patient for treatingfibromyalgia in combination with a therapy or another therapeutic agentknown or believed to be effective in treating fibromyalgia, or incertain embodiments, a disease, disorder, or condition associated withfibromyalgia. Drug therapy for fibromyalgia may be tailored to theseverity and frequency of fibromyalgia episodes. For occasionalepisodes, acute treatment may be indicated. For fibromyalgia episodesoccurring two or more times per month, or when attacks greatly impactthe patient's daily life, chronic therapy on an ongoing basis may beappropriate.

Treatments for fibromyalgia that reduce the frequency of episodes andwhich may be administered in conjunction with crystalline(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid anhydrate and/or crystalline(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid hemihydrate include non-steroidal anti-inflammatory agents(NSAIDs), adrenergic beta-blockers, calcium channel blockers, tricyclicantidepressants, selective serotonin reuptake inhibitors,anticonvulsants, NMDA receptor antagonists, dopamine agonists, selective5-HT₃ receptor antagonists, opioids, muscle relaxants, sedativehypnotics, and other therapy. Examples of NSAIDs useful for treatingfibromyalgia and which may be administered in conjunction withcrystalline(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid anhydrate and/or crystalline(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid hemihydrate include aspirin, ibuprofen, fenoprofen, flurbiprofen,ketoprofen, mefenamic acid, and naproxen. Examples of adrenergicbeta-blockers useful for treating fibromyalgia and which may beadministered in conjunction with crystalline(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid anhydrate and/or crystalline(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid hemihydrate include acebutolol, atenolol, imilol, metoprolol,nadolol, pindolol, propranolol, and timolol. Examples of calcium channelblockers useful for treating fibromyalgia and which may be administeredin conjunction with crystalline(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid anhydrate and/or crystalline(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid hemihydrate include amlodipine, diltiazem, dotarizine, felodipine,flunarizine, nicardipine, nifedipine, nimodipine, nisoldipine, andverapamil. Examples of tricyclic antidepressants useful for treatingfibromyalgia and which may be administered in conjunction withcrystalline(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid anhydrate and/or crystalline(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid hemihydrate include amitriptyline, desipramine, doxepin,imipramine, nortriptyline, cyclobenzaprine, and protriptyline. Examplesof selective serotonin reuptake inhibitors useful for treatingfibromyalgia and which may be administered in conjunction withcrystalline(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid anhydrate and/or crystalline(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid hemihydrate include fluoxetine, methysergide, nefazodone,paroxetine, sertraline, citalopram, and venlafaxine. Examples of otherantidepressants useful for treating g fibromyalgia and which may beadministered in conjunction with crystalline(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid anhydrate and/or crystalline(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid hemihydrate include bupropion, nefazodone, norepinephrine,venlafaxine, duloxetine, and trazodone. Examples of anticonvulsants(antiepileptics) useful for treating fibromyalgia and which may beadministered in conjunction with crystalline(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid anhydrate and/or crystalline(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid hemihydrate include divalproex sodium, felbamate, gabapentin,lamotrigine, levetiracetam, oxcarbazepine, tiagabine, topiramate,valproate, and zonisamide. Examples of NMDA receptor antagonists usefulfor treating fibromyalgia and which may be administered in conjunctionwith crystalline(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid anhydrate and/or crystalline(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid hemihydrate include dextromethorphan, magnesium, and ketamine.Examples of dopamine agonists useful for treating fibromyalgia and whichmay be administered in conjunction with crystalline(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid anhydrate and/or crystalline(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid hemihydrate include α-dihydroergocryptine. Examples of opioidsuseful for preventing fibromyalgia and which may be administered inconjunction with crystalline(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid anhydrate and/or crystalline(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid hemihydrate are tramadol, oxycodone, and methadone. An example of amuscle relaxant useful for treating fibromyalgia and which may beadministered in conjunction with crystalline(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid anhydrate and/or crystalline(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid hemihydrate is cyclobenzaprine. Examples of therapies useful fortreating fibromyalgia and which may be administered in conjunction withcrystalline(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid anhydrate and/or crystalline(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid hemihydrate include exercise, interferon, growth hormone, hormonetherapy, diet low in animal fat and high in fiber, and complementarytherapies such as counseling/psychotherapy, relaxation training,progressive muscle relaxation, guided imagery, diaphragmatic breathing,biofeedback, acupuncture, and physical and massage therapy.

Acute fibromyalgia treatments intended to eliminate or reduce theseverity of muscular/skeletal pain and any associated symptoms, andwhich may be administered in conjunction with crystalline(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid anhydrate and/or crystalline(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid hemihydrate, include serotonin receptor agonists, such as triptans(5-hydroxytryptophan (5-HTP) agonists), for example, almotriptan,eletriptan, frovatriptan, naratriptan, rizatriptan, sumatriptan, andzolmitriptan; ergotamine-based compounds such as dihydroergotamine andergotamine; antiemetics such as metoclopramide and prochlorperazine; andcompounds that provide analgesic effects.

Other examples of drugs useful in treating fibromyalgia and which may beadministered in conjunction with crystalline(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid anhydrate and/or crystalline(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid hemihydrate include acetaminophen-aspirin, caffeine,cyproheptadine, methysergide, valproic acid; NSAIDs such as diclofenac,flurbiprofen, ketaprofen, ketorolac, ibuprofen, indomethacin,meclofenamate, and naproxen sodium; opioids such as codeine, meperidine,and oxycodone; and glucocorticoids such as dexamethasone, prednisone,and methylprednisolone.

In certain embodiments, crystalline(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid anhydrate and/or crystalline(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid hemihydrate may be administered to a patient for treatingmusculoskeletal pain in combination with a therapy or anothertherapeutic agent known or believed to be effective in treatingmusculoskeletal pain. Examples of drugs useful for treatingmusculoskeletal pain and which may be administered in conjunction withcrystalline(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid anhydrate and/or crystalline(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid hemihydrate include cyclobenzaprine, dantrolene, methocarbamol,orphenadrine, tizanidrine, metaxalone, carisoprodol, chlorphenesin,chlorzoxazone, alprazolam, bromazepam, chlordiazepoxide, clorazepate,diazepam, flunitriazepam, lorazepam, medazepam, midazolam, oxazepam,prazepam, triazolam, temazepam, and botulinum toxin. In certainembodiments, any of the drugs useful for treating neuropathic pain maybe coadministered with a prodrug of a GABA_(B) agonist for treatingmusculoskeletal pain.

In certain embodiments, crystalline(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid anhydrate and/or crystalline(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid hemihydrate may be administered to a patient for treating low backpain in combination with a therapy or another therapeutic agent known orbelieved to be effective in treating low back pain. Examples of drugsuseful for treating low back pain and which may be administered inconjunction with crystalline(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid anhydrate and/or crystalline(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid hemihydrate include NSAIDs such as aspirin, naproxen, andibuprofen; anticonvulsants; antidepressants such as amitriptyline anddesipramine; and opioids such as codeine, oxycodone, hydrocodone, andmorphine. In certain embodiments, any of the drugs useful for treatingneuropathic pain may be coadministered with a prodrug of a GABA_(B)agonist for treating low back pain. Therapies for low back pain andwhich may be administered in conjunction with crystalline(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid anhydrate and/or crystalline(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid hemihydrate include the use of cold and hot compresses, bed rest,exercise, spinal manipulation, acupuncture, biofeedback, interventionaltherapy, traction, transcutaneous electrical nerve stimulation,ultrasound, vertebroplasty, kyphoplasty, discectomy, foraminotomy,intradiscal electrothermal therapy, nucleoplasty, radiofrequencylesioning, spinal fusion, and spinal laminectomy.

In certain embodiments, crystalline(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid anhydrate and/or crystalline(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid hemihydrate may be administered to a patient for treating low backpain in combination with a therapy or other therapeutic agent fortreating muscle spasms, for example muscle spasms associated with lowback pain, such as muscle relaxants. Examples of drugs useful as musclerelaxants for treating muscle spasms and which may be administered inconjunction with crystalline(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid anhydrate and/or crystalline(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid hemihydrate include baclofen, carisoprodol, chlorzoxazone,cyclobenzaprine, diazepam, metaxalone, methocarbamol, orphenadrine, andtizanidine.

EXAMPLES

The following examples describe in detail the preparation, properties,and uses of crystalline(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid anhydrate and crystalline(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid hemihydrate. It will be apparent to those skilled in the art thatmany modifications, both to materials and methods, may be practicedwithout departing from the scope of the disclosure.

Example 1 Synthesis of(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid (1) and(3R)-4-{[(1R)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid; and Separation by Crystallization

To 3 moles of 2-methyl-1-(methylthiocarbonyloxy)propyl isobutyrate isadded N-hydroxysuccinimide and a mixture of dichloromethane andperacetic acid. The mixture is cooled to 15° C. during the addition ofthe mixture of dichloromethane and peracetic acid.1-((2,5-dioxopyrrolidin-1-yl-oxycarbonyloxy)-2-methylpropyl)-2-methylpropanoate(3) is extracted from the final solution via cold water extraction. Tothe extracted compound (3) a 1:1 mixture of isopropyl alcohol:hexane isadded and the mixture cooled in a dry-ice bath. Compound (3)crystallizes in this reaction mixture. The product is collected byfiltration and dried to afford 470 g (53%) of crystalline1-((2,5-dioxopyrrolidin-1-yl-oxycarbonyloxy)-2-methylpropyl)-2-methylpropanoate(3).

To a 500 mL, round bottomed flask, is added 21.3 g (R)-baclofen (2) and30.1 g compound (3). The two compounds are mixed and a mixture of 100 mLacetonitrile and 100 mL water is added at room temperature. The reactionis stirred at room temperature for 4 hours. The reaction mixture isdiluted with 500 mL methyl tert-butyl ether, washed twice with 200 mLwater, and washed once with 100 mL of brine. The methyl tert-butyl etherlayer is dried to afford a mixture of(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid (1) and(3R)-4-{[(1R)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid.

To 40 g of the mixture of(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid (1) and(3R)-4-{[(1R)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid is added 800 mL of a 1:1 mixture of toluene:methylcyclohexane.(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid (1) crystallizes in this reaction mixture to afford 13 g (65%) ofcrystalline compound (1). This crystallization reaction separates(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid (1) from(3R)-4-{[(1R)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid.

Example 2 Separation of(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid (1) from(3R)-4-{[(1R)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid by Crystallization From 3:1 Toluene:Methylcyclohexane

A portion of the mixture of(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid (1) and(3R)-4-{[(1R)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid produced according to Example 1 is separated as follows: to 110 gof the mixture of(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid (1) and(3R)-4-{[(1R)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid is added 3.3 L of a 3:1 mixture of toluene:methylcyclohexane.(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid (1) crystallizes in this reaction mixture to afford 88 g (80%) ofcrystalline compound (1).

A second crystallization is performed as follows: to 20 g of the mixtureof(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid (1) and(3R)-4-{[(1R)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid produced according to Example 1 is added 400 mL of a 3:1 mixture oftoluene:methylcyclohexane.(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid (1) crystallizes in this reaction mixture to afford 5 g (25%) ofcrystalline compound (1).

From 1.5:1 Methanol:Water

A portion of the mixture of(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid (1) and(3R)-4-{[(1R)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid produced according to Example 1 is separated as follows: 40 g ofthe mixture of(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid (1) and(3R)-4-{[(1R)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid is dissolved in a mixture of 150 mL methanol and 100 mL water. Themixture is heated to 60° C. and then cooled to room temperature. Theheating and cooling procedure is performed 5 times in succession toyield 6 g (30%) of crystalline(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid (1).

Example 3 Crystallization of(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid hemihydrate (1b)

A 2,500 L reaction vessel was charged with 313 L of methyl tert-butylether (MTBE) and 224 L of water, to which was added 100 kg of(R)-baclofen and 134 kg of1-((2,5-dioxopyrrolidin-1-yl-oxycarbonyloxy)-2-methylpropyl)-2-methylpropanoate(3) at 20° C. The charging lock and the reactor walls were each rinsedwith 67 liters of MTBE. The reaction mixture was heated to 45° C. andstirred for 6.25 hours. The reaction mixture was then cooled to 20° C.,the aqueous phase was separated and discarded. The organic phase waswashed with 224 kg of 1N hydrochloric acid, followed by two washes with224 kg of water each. The product-containing organic phase was filteredthrough a charcoal cartridge. The reactor and lines were rinsed with 137liters of MTBE, which was also filtered through the charcoal filter andcombined with the previous filtrate. The combined organic phase waswashed once more with 224 kg of water.

To the filtrate was added 277 L of methylcyclohexane, and 67 L of MTBEfollowed by an additional 768 L of methylcyclohexane. The resultingmixture was heated to 50° C. to dissolve all solids. The solution wasthen cooled to 35° C. within one hour and seeded with 0.25 kg of(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid hemihydrate (1b). The resulting mixture was cooled to 5° C. over aperiod of ten hours. Crystalline(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid hemihydrate (1b) was isolated via centrifugation, washed with amixture of 34.4 kilograms of MTBE and 82.6 kg of methylcyclohexane, anddried at a temperature between 45° C. to 75° C. using a vacuum of 25 to50 mbar. This resulted in 51.75 kg of crystalline(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid hemihydrate (1b).

Example 4 Crystallization of(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid anhydrate (1a)

To a 2,500 L reactor was added 51.1 kg of crystalline(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid hemihydrate (1b) and 104.4 kg of acetone, at 35° C. To this mixturewas added 247.15 kg of hexane and the mixture was heated to 50° C. andstirred for 10 minutes at this temperature. The temperature was thenreduced to 45° C. Thereafter 98 kg of hexane was added, followed by 50 gof(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid anhydrate seed crystals. A further 488.4 kg of hexane was added at45° C. and the mixture was cooled to 0° C. within 2.5 hours. Crystalline(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid anhydrate was isolated via centrifugation, washed with a mixture of168.1 kg of hexane in 23 L of acetone, and dried at 50° C. using avacuum of 22-49 mbar for 15 hours. This resulted in 45.15 kg of(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid anhydrate.

Example 5 Differential Scanning calorimetry of Crystalline(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid hemihydrate (1b)

Differential scanning calorimetry was performed using a Perkin ElmerDSC-7 instrument. DSC on the hemihydrate was carried out in a goldsample pan sealed in air. Heating occurred at a rate of 20K/min over atemperature range of 0° C.-150° C.

Crystalline(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid hemihydrate prepared according to Example 3 exhibited two distinctmelt transitions. The first melt transition occurred from about 70° C.to about 110° C., with a peak maximum at about 100° C. and a ΔH of about58.3 J/g. The second melt transition occurred from about 110° C. toabout 125° C., with a peak maximum at about 115° C. and a ΔH of about39.1 J/g.

The lower melting peak near 100° C. corresponds to melting ofcrystalline(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid hemihydrate, while the second melting peak near 115° C. correspondsto the melting of crystalline(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid anhydrate, which exhibits a depressed melting point in this case,because of the presence of water released from the hemihydrate.

Example 6 Thermogravimetric Analysis of Crystalline(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid hemihydrate (1b)

Thermogravimetric measurements were carried out with a NetzschThermo-Microbalance TG 209 coupled to a Bruker FTIR Spectrometer Vector22. The sample was contained in sample pans with a pinhole, under a N₂atmosphere. The heating rate was set at 10 K/min.

Crystalline(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid hemihydrate prepared according to Example 3 exhibited a weight lossof about 2.1% up to 170° C. when heated at a scan rate of 10 K/min. Thisweight loss, which occurred predominantly between 80° C. and 130° C., isattributable to water.

Under the conditions used for TG-FTIR thermal decomposition began slowlyat about 170° C. and increased strongly above 190° C.

Example 7 X-Ray Powder Diffraction Analysis of Crystalline(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid hemihydrate (1b)

X-ray powder diffraction analyses were performed using a Bruker D8Advance powder X-ray diffractometer using CuKα radiation. 2θ values areaccurate within an error of ±0.1-0.2°. The tube voltage and amperagewere set to 35 kV and 45 mA, respectively. The step size was set at0.017° (2θ), the step time was set at 105±5 sec, and the scanning rangewas 2°-50° (2θ). The samples were rotated. Differential radiation wasdetected by a VANTEC1 detector having an opening angle of 3° and a totalnumber of active channels of 360±10. The y-axis (counts or CPS) of thediffractogram depicted in FIG. 1 does not show the total intensity(/sec)but rather the value intensity/number of active detector channels(/sec).Sample holders were silicon single crystal and sample dimensions were adepth/diameter: 0.1 mm/˜12 mm.

The X-ray powder diffractogram for crystalline(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid hemihydrate prepared according to Example 3 is shown in FIG. 1. Thecharacteristic scattering angles for the same crystalline preparationshown in FIG. 1 are presented in Table 1.

TABLE 1 XRPD Scattering Angles. θ2θ (deg)  4.04° ± 0.2°  6.47° ± 0.2° 7.97° ± 0.2°  9.46° ± 0.2° 10.10° ± 0.2° 10.87° ± 0.2° 12.88° ± 0.2°15.68° ± 0.2° 16.72° ± 0.2° 18.16° ± 0.2° 18.91° ± 0.2° 19.33° ± 0.2°19.96° ± 0.2° 20.23° ± 0.2° 20.62° ± 0.2° 21.76° ± 0.2° 22.42° ± 0.2°23.55° ± 0.2° 24.02° ± 0.2° 25.13° ± 0.2° 25.61° ± 0.2° 26.09° ± 0.2°28.07° ± 0.2° 28.53° ± 0.2° 29.87° ± 0.2° 30.45° ± 0.2° 30.74° ± 0.2°31.52° ± 0.2° 32.60° ± 0.2° 35.94° ± 0.2° 36.63° ± 0.2°

Example 8 Raman Spectroscopy Analysis of Crystalline(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid hemihydrate (1b)

FT-Raman spectra were recorded on a Bruker RFS 100 FT-Raman system witha near infrared Nd:YAG laser operating at 1064 nm and a liquidnitrogen-cooled germanium detector. A total of 64 scans with aresolution of 2 cm⁻¹ were accumulated in the range from 3500 to 50 cm⁻¹.In general, 100 mW laser power was used. Dispersive Raman spectra weretaken on a Renishaw RM 1000 System using a 20× long working distanceobjective lens in conjunction with a diode laser operating at 785 nm.The measurements were carried out over the range 2000 cm⁻¹ to 100 cm⁻¹.

The Raman spectrum for crystalline(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid hemihydrate prepared according to Example 3 is shown in FIG. 2.

The most prominent bands were found at 1744 cm⁻¹, 1600 cm⁻¹, 1453 cm⁻¹,1290 cm⁻¹, 1238 cm⁻¹, 1201 cm⁻¹, 954 cm⁻¹, 872 cm⁻¹, 779 cm⁻¹, 635 cm⁻¹,362 cm⁻¹, 315 cm⁻¹, 110 cm⁻¹, and 84 cm⁻¹. The band at 110 cm⁻¹ was thestrongest Raman spectrum band displayed.

Example 9 Differential Scanning Calorimetry of Crystalline(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid anhydrate (1a)

Differential scanning calorimetry was performed using a Perkin ElmerDSC-7 instrument. DSC on the hemihydrate was carried out in a goldsample pan sealed under nitrogen. Heating occurred at a rate of 20K/minover a temperature range of 0° C.-150° C.

Crystalline(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid anhydrate prepared according to the methods of the presentdisclosure exhibited a single melt transition from about 120° C. toabout 145° C., with a peak maximum at about 131° C. and a ΔH of about92.6 J/g.

Example 10 Thermogravimetric Analysis of Crystalline(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid anhydrate (1a)

Thermogravimetric measurements were carried out with a NetzschThermo-Microbalance TG 209 coupled to a Bruker FTIR Spectrometer Vector22. The sample was contained in sample pans with a pinhole, under a N₂atmosphere. The heating rate was set at 10 K/min.

Crystalline(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid anhydrate prepared according to the methods of the presentdisclosure showed very little weight loss up to 180° C. when heated at ascan rate of 10 K/min.

Under the conditions used for TG-FTIR, thermal decomposition beganslowly at about 170° C. and increased strongly above 190° C.

Example 11 X-Ray Powder Diffraction Analysis of Crystalline(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid anhydrate (1a)

X-ray powder diffraction analyses were performed using a Bruker D8Advance powder X-ray diffractometer using CuKα radiation. 2θ values areaccurate within an error of ±0.1-0.2°. The tube voltage and amperagewere set to 35 kV and 45 mA, respectively. The step size was set at0.017° (2θ), the step time was set at 105±5 sec, and the scanning rangewas 2°-50° (2θ). The samples were rotated. Differential radiation wasdetected by a VANTEC1 detector having an opening angle of 3° and a totalnumber of active channels of 360±10. The y-axis (counts or CPS) of thediffractogram depicted in FIG. 3 does not show the total intensity(/sec)but rather the value intensity/number of active detector channels(/sec).Sample holders were silicon single crystal and sample dimensions were adepth/diameter: 0.1 mm/˜12 mm.

The X-ray powder diffractogram for crystalline(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid anhydrate prepared according to the methods of the presentdisclosure is shown in FIG. 3. The characteristic scattering angles forthe same crystalline preparation shown in FIG. 3 are presented in Table2.

TABLE 2 XRPD Scattering Angles. θ2θ (deg)  4.33° ± 0.2°  4.76° ± 0.2° 5.83° ± 0.2°  6.93° ± 0.2°  9.07° ± 0.2°  9.46° ± 0.2° 10.54° ± 0.2°11.06° ± 0.2° 11.61° ± 0.2° 12.94° ± 0.2° 15.25° ± 0.2° 16.55° ± 0.2°17.46° ± 0.2° 17.84° ± 0.2° 18.01° ± 0.2° 18.41° ± 0.2° 18.69° ± 0.2°18.93° ± 0.2° 19.36° ± 0.2° 20.01° ± 0.2° 20.46° ± 0.2° 21.26° ± 0.2°21.75° ± 0.2° 22.19° ± 0.2° 22.56° ± 0.2° 23.35° ± 0.2° 23.85° ± 0.2°24.84° ± 0.2° 25.96° ± 0.2° 26.78° ± 0.2° 27.29° ± 0.2° 28.69° ± 0.2°29.39° ± 0.2° 31.22° ± 0.2° 32.35° ± 0.2° 33.47° ± 0.2° 34.62° ± 0.2°36.08° ± 0.2°

Example 12 Raman Spectroscopy Analysis of Crystalline(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid anhydrate (1a)

FT-Raman spectra were recorded on a Bruker RFS 100 FT-Raman system witha near infrared Nd:YAG laser operating at 1064 nm and a liquidnitrogen-cooled germanium detector. A total of 64 scans with aresolution of 2 cm⁻¹ were accumulated in the range from 3500 to 50 cm⁻¹.In general, 100 mW laser power was used. Dispersive Raman spectra weretaken on a Renishaw RM 1000 System using a 20× long working distanceobjective lens in conjunction with a diode laser operating at 785 nm.The measurements were carried out over the range 2000 cm⁻¹ to 100 cm⁻¹.

The Raman spectrum for crystalline(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid anhydrate prepared according to the methods of the presentdisclosure is shown in FIG. 4.

The most prominent bands were found at 1747 cm⁻¹, 1599 cm⁻¹, 1447 cm⁻¹,1412 cm⁻¹, 1335 cm⁻¹, 1203 cm⁻¹, 1092 cm⁻¹, 954 cm⁻¹, 868 cm⁻¹, 798cm⁻¹, 637 cm⁻¹, 401 cm⁻¹, 348 cm⁻¹, 317 cm⁻¹, 244 cm⁻¹, 119 cm⁻¹, and 85cm⁻¹. The band at 119 cm⁻¹ was the strongest Raman spectrum banddisplayed.

Finally, it should be noted that there are alternative ways ofimplementing the embodiments disclosed herein. Accordingly, the presentembodiments are to be considered as illustrative and not restrictive.Furthermore, the claims are not to be limited to the details givenherein, and are entitled their full scope and equivalents thereof.

1-20. (canceled)
 21. Crystalline(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid anhydrate exhibits characteristic scattering angles (2Θ) at leastat 4.33°±0.2°, 4.76°±0.2°, 11.06°±0.2° and 11.61°±0.2° in an X-raypowder diffractogram measured using Cu-K_(α) radiation.
 22. Thecrystalline(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid anhydrate of claim 21, comprising characteristic scattering angles(2Θ) at least at 4.33°±0.2°, 4.76°±0.2°, 5.83°±0.2°, 9.07°±0.2°,9.46°±0.2°, 10.54°±0.2°, 11.06°±0.2°, 11.61°±0.2°, 12.94°±0.2°,17.46°±0.2°, 17.84°±0.2°, 18.01°±0.2°, 19.36°±0.2°, 20.01°±0.2° and21.26°±0.2° in an X-ray powder diffractogram measured using Cu-K_(α)radiation.
 23. The crystalline(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid anhydrate of claim 21, comprising characteristic scattering angles(2Θ) at least at 4.33°±0.2°, 4.76°±0.2°, 5.83°±0.2°, 6.93°±0.2°,9.07°±0.2°, 9.46°±0.2°, 10.54°±0.2°, 11.06°±0.2°, 11.61°±0.2°,12.94°±0.2°, 15.25°±0.2°, 16.55°±0.2°, 17.46°±0.2°, 17.84°±0.2°,18.01°±0.2°, 18.41°±0.2°, 18.69°±0.2°, 18.93°±0.2°, 19.36°±0.2°,20.01°±0.2°, 20.46°±0.2°, 21.26°±0.2°, 21.75°±0.2°, 22.19°±0.2°,22.56°±0.2°, 23.35°±0.2°, 23.85°±0.2°, 24.84°±0.2°, 25.96°±0.2°,26.78°±0.2°, 27.29°±0.2°, 28.69°±0.2°, 29.39°±0.2°, 31.22°±0.2°,32.35°±0.2°, 33.47°±0.2°, 34.62°±0.2° and 36.08°±0.2° in an X-ray powderdiffractogram measured using Cu-K_(α) radiation.
 24. The crystalline(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid anhydrate of claim 21, which exhibits a strong characteristic Ramanspectrum band at 119 cm⁻¹.
 25. The crystalline(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid anhydrate of claim 21, which exhibits characteristic Raman spectrumbands at least at 119 cm⁻¹ and 85 cm⁻¹.
 26. The crystalline(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid anhydrate of claim 21, which exhibits characteristic Raman spectrumbands at least at 1599 cm⁻¹, 1447 cm⁻¹, 798 cm⁻¹, 119 cm⁻¹ and 85 cm⁻¹.27. The crystalline(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid anhydrate of claim 21, which exhibits characteristic Raman spectrumbands at least at 1747 cm⁻¹, 1599 cm⁻¹, 1447 cm⁻¹, 1412 cm⁻¹, 1335 cm⁻¹,1203 cm⁻¹, 1092 cm⁻¹, 954 cm⁻¹, 868 cm⁻¹, 798 cm⁻¹, 637 cm⁻¹, 401 cm⁻¹,348 cm⁻¹, 317 cm⁻¹, 244 cm⁻¹, 119 cm⁻¹ and 85 cm⁻¹.
 28. The crystalline(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid anhydrate of claim 21, which has a critical water activity of lessthan or equal to about 0.75±0.05.
 29. The crystalline(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid anhydrate of claim 21, which undergoes thermal decomposition at atemperature ranging from about 170° C. to about 190° C. using athermogravimetric analyzer coupled with a Fourier-transform infraredspectrometer at a scan rate of about 10 K/min.
 30. The crystalline(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid anhydrate of claim 21, which undergoes a melt/phase transition at atemperature ranging from about 120° C. to about 140° C. usingdifferential scanning calorimetry at a heating rate of 20 K/min.
 31. Thecrystalline(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid anhydrate of claim 30, wherein the melt/phase transition occurs atabout 131° C. using differential scanning calorimetry at a heating rateof 20 K/min.
 32. The crystalline(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid anhydrate of claim 30, wherein the melt/phase transition occurs atabout 131.3° C. using differential scanning calorimetry at a heatingrate of 20 K/min.
 33. The crystalline(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid anhydrate of claim 21, which contains less than about 0.05 wt %water at 50% relative humidity as measured by dynamic vapor sorption.34. The crystalline(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid anhydrate of claim 21, which contains less than about 0.1 wt %water at 95% relative humidity as measured by dynamic vapor sorption.35. A pharmaceutical composition comprising the crystalline(3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoicacid anhydrate of claim 21 and a pharmaceutically acceptable vehicle.36. The pharmaceutical composition of claim 35, wherein thepharmaceutical composition is a sustained release oral dosageformulation.
 37. A method of treating a disease or disorder in a patientcomprising administering to a patient in need of such treatment atherapeutically effective amount of the pharmaceutical composition ofclaim 35, wherein the disease or disorder is selected from spasticity,gastroesophageal reflux disease, emesis, cough, substance addiction andabuse, neuropathic pain and musculoskeletal pain.
 38. The method ofclaim 37, wherein the pharmaceutical composition is a sustained releaseoral dosage formulation.
 39. A kit comprising the pharmaceuticalcomposition of claim 35 and instructions for administering thepharmaceutical composition to a patient in need thereof for treating adisease or disorder selected from spasticity, gastroesophageal refluxdisease, emesis, cough, substance addiction and abuse, neuropathic painand musculoskeletal pain.